首页 > 最新文献

BMC Biology最新文献

英文 中文
Species specificity and specificity diversity (SSD) framework: a novel method for detecting the unique and enriched species associated with disease by leveraging the microbiome heterogeneity. 物种特异性和特异性多样性(SSD)框架:一种利用微生物组异质性检测与疾病相关的独特和丰富物种的新方法。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-12-05 DOI: 10.1186/s12915-024-02024-7
Zhanshan Sam Ma

Background: Differentiating the microbiome changes associated with diseases is challenging but critically important. Majority of existing efforts have been focused on a community level, but the discerning power of community or holistic metrics such as diversity analysis seems limited. This prompts many researchers to believe that the promise should be downward to species or even strain level-effectively and efficiently identifying unique or enriched species in diseased microbiomes with statistical rigor. Nevertheless, virtually, all species-level approaches such as differential abundance and differential network analysis methods exclusively rely on species abundances without considering species distribution information, while it can be said that distribution is equally, if not more, important than abundance in shaping the spatiotemporal heterogeneity of community compositions.

Results: Here, we fill the gap by developing a novel framework-species specificity and specificity diversity (SSD)-that synthesizes both abundance and distribution information to differentiate microbiomes, at both species and community scales, under different environmental gradients such as the healthy and diseased treatments. The proposed SSD framework consists of three essential elements. The first is species specificity (SS), a concept that reincarnates the traditional specialist-generalist continuum and is defined by Mariadassou et al. (Ecol Lett 18:974-82, 2015). The SS synthesizes a species' local prevalence (distribution) and global abundance information and attaches specificity measure to each species in a specific habitat (e.g., healthy or diseased treatment). The second element is a new concept to introduce here, the (species) specificity diversity (SD), which is inspired by traditional species (abundance) diversity in community ecology and measures the diversity of specificity (a proxy for metacommunity heterogeneity, essentially) with Renyi's entropy. The third element is a pair of statistical tests based on the principle of permutation tests.

Conclusions: The SSD framework can (i) identify and catalogue lists of unique species (US), significantly enriched species (ES) in each treatment based on SS and specificity permutation (SP) test and (ii) measure the holistic differences between assemblages (or treatments) based on SD and specificity diversity permutation (SDP) test. Both capacities can be enabling technologies for general comparative microbiome research including risk assessment, diagnosis, and treatment of microbiome-associated diseases.

背景:区分与疾病相关的微生物组变化具有挑战性,但至关重要。大多数现有的努力都集中在社区层面,但社区或整体指标(如多样性分析)的辨别能力似乎有限。这促使许多研究人员相信,前景应该下降到物种甚至菌株水平-有效和高效地识别患病微生物组中独特或富集的物种,并具有统计严密性。然而,实际上,所有物种水平的方法,如差异丰度和差异网络分析方法,都只依赖于物种丰度,而不考虑物种分布信息,而可以说,在形成群落组成的时空异质性方面,分布与丰度同等重要,甚至更重要。结果:在这里,我们通过建立一个新的框架——物种特异性和特异性多样性(SSD)来填补这一空白,该框架综合了丰度和分布信息,以区分不同环境梯度(如健康和患病处理)下的物种和群落尺度上的微生物组。拟议的固态硬盘框架包括三个基本要素。首先是物种特异性(SS),这是一个由Mariadassou等人定义的概念,体现了传统的专家-通才连续体(Ecol Lett:974- 82,2015)。SS综合了物种的本地流行(分布)和全球丰度信息,并对特定栖息地的每个物种(例如,健康或患病处理)附加特异性措施。第二个要素是本文引入的一个新概念,即(物种)特异性多样性(SD),该概念受到群落生态学中传统物种(丰度)多样性的启发,用Renyi熵来衡量特异性多样性(本质上是元群落异质性的代表)。第三个要素是基于排列检验原理的一对统计检验。结论:SSD框架可以(i)基于SS和特异性排列(SP)检验识别和编目各处理的独特物种(US)、显著富集物种(ES)清单;(ii)基于SD和特异性多样性排列(SDP)检验衡量组合(或处理)之间的整体差异。这两种能力都可以成为促进微生物组一般比较研究的技术,包括微生物组相关疾病的风险评估、诊断和治疗。
{"title":"Species specificity and specificity diversity (SSD) framework: a novel method for detecting the unique and enriched species associated with disease by leveraging the microbiome heterogeneity.","authors":"Zhanshan Sam Ma","doi":"10.1186/s12915-024-02024-7","DOIUrl":"10.1186/s12915-024-02024-7","url":null,"abstract":"<p><strong>Background: </strong>Differentiating the microbiome changes associated with diseases is challenging but critically important. Majority of existing efforts have been focused on a community level, but the discerning power of community or holistic metrics such as diversity analysis seems limited. This prompts many researchers to believe that the promise should be downward to species or even strain level-effectively and efficiently identifying unique or enriched species in diseased microbiomes with statistical rigor. Nevertheless, virtually, all species-level approaches such as differential abundance and differential network analysis methods exclusively rely on species abundances without considering species distribution information, while it can be said that distribution is equally, if not more, important than abundance in shaping the spatiotemporal heterogeneity of community compositions.</p><p><strong>Results: </strong>Here, we fill the gap by developing a novel framework-species specificity and specificity diversity (SSD)-that synthesizes both abundance and distribution information to differentiate microbiomes, at both species and community scales, under different environmental gradients such as the healthy and diseased treatments. The proposed SSD framework consists of three essential elements. The first is species specificity (SS), a concept that reincarnates the traditional specialist-generalist continuum and is defined by Mariadassou et al. (Ecol Lett 18:974-82, 2015). The SS synthesizes a species' local prevalence (distribution) and global abundance information and attaches specificity measure to each species in a specific habitat (e.g., healthy or diseased treatment). The second element is a new concept to introduce here, the (species) specificity diversity (SD), which is inspired by traditional species (abundance) diversity in community ecology and measures the diversity of specificity (a proxy for metacommunity heterogeneity, essentially) with Renyi's entropy. The third element is a pair of statistical tests based on the principle of permutation tests.</p><p><strong>Conclusions: </strong>The SSD framework can (i) identify and catalogue lists of unique species (US), significantly enriched species (ES) in each treatment based on SS and specificity permutation (SP) test and (ii) measure the holistic differences between assemblages (or treatments) based on SD and specificity diversity permutation (SDP) test. Both capacities can be enabling technologies for general comparative microbiome research including risk assessment, diagnosis, and treatment of microbiome-associated diseases.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"283"},"PeriodicalIF":4.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CRISPR/Cas9-induced double-strand breaks in the huntingtin locus lead to CAG repeat contraction through DNA end resection and homology-mediated repair. CRISPR/ cas9诱导的huntingtin位点双链断裂通过DNA末端切除和同源性介导的修复导致CAG重复收缩。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-12-03 DOI: 10.1186/s12915-024-02079-6
Pawel Sledzinski, Mateusz Nowaczyk, Marianna Iga Smielowska, Marta Olejniczak

Background: The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences.

Results: The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair.

Conclusions: Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells.

背景:CAG/CTG重复序列在功能不相关基因中的扩增是许多遗传性神经退行性疾病的致病因素,包括亨廷顿病(HD)、脊髓小脑共济失调(SCAs)和1型肌强直性营养不良(DM1)。尽管多年的研究,负责重复不稳定性的机制尚不清楚,最近的发现表明DNA修复在这一过程中的关键作用。在酵母模型中,基因组编辑工具诱导的dsb修复导致长CAG/CTG重复序列的缩短。了解这一机制是开发基于重复序列控制缩短的治疗策略的第一步。本研究的目的是表征人细胞内源性HTT位点cas9诱导的DSB修复产物,并确定影响特定类型序列形成的因素。结果:卵裂位点的位置和周围序列影响DNA修复的结果。CAG重复序列内的dsb导致约90%的产物帧内重复序列缩短。这种收缩的机制涉及MRE11-CTIP和RAD51活性以及DNA末端切除。我们证明了位于CAG重复序列上游的DSB诱导聚合酶介导的末端连接,导致整个CAG链的缺失。此外,利用蛋白质组学分析,我们确定了可能参与CAG序列修复的新因子。结论:我们的研究为CRISPR/ cas9诱导人类细胞中CAG重复序列缩短的复杂机制提供了新的见解。
{"title":"CRISPR/Cas9-induced double-strand breaks in the huntingtin locus lead to CAG repeat contraction through DNA end resection and homology-mediated repair.","authors":"Pawel Sledzinski, Mateusz Nowaczyk, Marianna Iga Smielowska, Marta Olejniczak","doi":"10.1186/s12915-024-02079-6","DOIUrl":"10.1186/s12915-024-02079-6","url":null,"abstract":"<p><strong>Background: </strong>The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences.</p><p><strong>Results: </strong>The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair.</p><p><strong>Conclusions: </strong>Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"282"},"PeriodicalIF":4.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comprehensive analysis of the Kinetoplastea intron landscape reveals a novel intron-containing gene and the first exclusively trans-splicing eukaryote. 对kinetoplasa内含子景观的综合分析揭示了一个新的内含子基因和第一个完全反式剪接的真核生物。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-12-03 DOI: 10.1186/s12915-024-02080-z
Alexei Yu Kostygov, Karolína Skýpalová, Natalia Kraeva, Elora Kalita, Cameron McLeod, Vyacheslav Yurchenko, Mark C Field, Julius Lukeš, Anzhelika Butenko

Background: In trypanosomatids, a group of unicellular eukaryotes that includes numerous important human parasites, cis-splicing has been previously reported for only two genes: a poly(A) polymerase and an RNA helicase. Conversely, trans-splicing, which involves the attachment of a spliced leader sequence, is observed for nearly every protein-coding transcript. So far, our understanding of splicing in this protistan group has stemmed from the analysis of only a few medically relevant species. In this study, we used an extensive dataset encompassing all described trypanosomatid genera to investigate the distribution of intron-containing genes and the evolution of splice sites.

Results: We identified a new conserved intron-containing gene encoding an RNA-binding protein that is universally present in Kinetoplastea. We show that Perkinsela sp., a kinetoplastid endosymbiont of Amoebozoa, represents the first eukaryote completely devoid of cis-splicing, yet still preserving trans-splicing. We also provided evidence for reverse transcriptase-mediated intron loss in Kinetoplastea, extensive conservation of 5' splice sites, and the presence of non-coding RNAs within a subset of retained trypanosomatid introns.

Conclusions: All three intron-containing genes identified in Kinetoplastea encode RNA-interacting proteins, with a potential to fine-tune the expression of multiple genes, thus challenging the perception of cis-splicing in these protists as a mere evolutionary relic. We suggest that there is a selective pressure to retain cis-splicing in trypanosomatids and that this is likely associated with overall control of mRNA processing. Our study provides new insights into the evolution of introns and, consequently, the regulation of gene expression in eukaryotes.

背景:锥虫是一组单细胞真核生物,包括许多重要的人类寄生虫,在锥虫中,以前只报道了两个基因的顺式剪接:一个聚(a)聚合酶和一个RNA解旋酶。相反,反式剪接,涉及到一个剪接的前导序列的连接,几乎在每个蛋白质编码转录物中都观察到。到目前为止,我们对这一原生物群剪接的了解仅源于对少数医学相关物种的分析。在这项研究中,我们使用了包含所有描述的锥虫属的广泛数据集来研究含内含子基因的分布和剪接位点的进化。结果:我们发现了一个新的保守内含子基因,编码rna结合蛋白,普遍存在于动质体中。我们发现阿莫虫的动质体内共生体Perkinsela sp.代表了第一个完全没有顺式剪接,但仍然保留反式剪接的真核生物。我们还提供了在活动体中逆转录酶介导的内含子丢失、5'剪接位点的广泛保存以及在保留的锥虫内含子子集中存在非编码rna的证据。结论:在kinetoplasa中发现的所有三个含内含子的基因都编码rna相互作用蛋白,具有微调多个基因表达的潜力,从而挑战了这些原生生物中顺式剪接仅仅是进化遗迹的看法。我们认为在锥虫体内存在保留顺式剪接的选择性压力,这可能与mRNA加工的总体控制有关。我们的研究为真核生物中内含子的进化以及基因表达的调控提供了新的见解。
{"title":"Comprehensive analysis of the Kinetoplastea intron landscape reveals a novel intron-containing gene and the first exclusively trans-splicing eukaryote.","authors":"Alexei Yu Kostygov, Karolína Skýpalová, Natalia Kraeva, Elora Kalita, Cameron McLeod, Vyacheslav Yurchenko, Mark C Field, Julius Lukeš, Anzhelika Butenko","doi":"10.1186/s12915-024-02080-z","DOIUrl":"10.1186/s12915-024-02080-z","url":null,"abstract":"<p><strong>Background: </strong>In trypanosomatids, a group of unicellular eukaryotes that includes numerous important human parasites, cis-splicing has been previously reported for only two genes: a poly(A) polymerase and an RNA helicase. Conversely, trans-splicing, which involves the attachment of a spliced leader sequence, is observed for nearly every protein-coding transcript. So far, our understanding of splicing in this protistan group has stemmed from the analysis of only a few medically relevant species. In this study, we used an extensive dataset encompassing all described trypanosomatid genera to investigate the distribution of intron-containing genes and the evolution of splice sites.</p><p><strong>Results: </strong>We identified a new conserved intron-containing gene encoding an RNA-binding protein that is universally present in Kinetoplastea. We show that Perkinsela sp., a kinetoplastid endosymbiont of Amoebozoa, represents the first eukaryote completely devoid of cis-splicing, yet still preserving trans-splicing. We also provided evidence for reverse transcriptase-mediated intron loss in Kinetoplastea, extensive conservation of 5' splice sites, and the presence of non-coding RNAs within a subset of retained trypanosomatid introns.</p><p><strong>Conclusions: </strong>All three intron-containing genes identified in Kinetoplastea encode RNA-interacting proteins, with a potential to fine-tune the expression of multiple genes, thus challenging the perception of cis-splicing in these protists as a mere evolutionary relic. We suggest that there is a selective pressure to retain cis-splicing in trypanosomatids and that this is likely associated with overall control of mRNA processing. Our study provides new insights into the evolution of introns and, consequently, the regulation of gene expression in eukaryotes.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"281"},"PeriodicalIF":4.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Protists and protistology in the Anthropocene: challenges for a climate and ecological crisis. 人类世的原生生物和原生生物学:气候和生态危机的挑战。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-12-02 DOI: 10.1186/s12915-024-02077-8
Abigail J Perrin, Richard G Dorrell

Eukaryotic microorganisms, or "protists," while often inconspicuous, play fundamental roles in the Earth ecosystem, ranging from primary production and nutrient cycling to interactions with human health and society. In the backdrop of accelerating climate dysregulation, alongside anthropogenic disruption of natural ecosystems, understanding changes to protist functional and ecological diversity is of critical importance. In this review, we outline why protists matter to our understanding of the global ecosystem and challenges of predicting protist species resilience and fragility to climate change. Finally, we reflect on how protistology may adapt and evolve in a present and future characterized by rapid ecological change.

真核微生物,或“原生生物”,虽然往往不引人注目,但在地球生态系统中发挥着重要作用,从初级生产和营养循环到与人类健康和社会的相互作用。在气候失调加速的背景下,随着自然生态系统的人为破坏,了解原生生物功能和生态多样性的变化至关重要。在这篇综述中,我们概述了为什么原生生物对我们对全球生态系统的理解很重要,以及预测原生生物物种对气候变化的恢复力和脆弱性所面临的挑战。最后,我们思考原生生物如何在当前和未来以快速的生态变化为特征的环境中适应和发展。
{"title":"Protists and protistology in the Anthropocene: challenges for a climate and ecological crisis.","authors":"Abigail J Perrin, Richard G Dorrell","doi":"10.1186/s12915-024-02077-8","DOIUrl":"10.1186/s12915-024-02077-8","url":null,"abstract":"<p><p>Eukaryotic microorganisms, or \"protists,\" while often inconspicuous, play fundamental roles in the Earth ecosystem, ranging from primary production and nutrient cycling to interactions with human health and society. In the backdrop of accelerating climate dysregulation, alongside anthropogenic disruption of natural ecosystems, understanding changes to protist functional and ecological diversity is of critical importance. In this review, we outline why protists matter to our understanding of the global ecosystem and challenges of predicting protist species resilience and fragility to climate change. Finally, we reflect on how protistology may adapt and evolve in a present and future characterized by rapid ecological change.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"279"},"PeriodicalIF":4.4,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. 小檗碱通过簇状细胞和苦味信号传导改善葡聚糖硫酸钠诱导的结肠炎。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-12-02 DOI: 10.1186/s12915-024-02078-7
Yuxuan Yang, Wenqing Li, Kaineng Sun, Siyu Sun, Yong Zhang, Lin Chen, Yangyue Ni, Min Hou, Zhipeng Xu, Lu Chen, Minjun Ji

Background: Inflammatory bowel disease (IBD), a persistent gastrointestinal disease, is featured with impaired gut immunity. Previous studies have demonstrated that tuft cells can regulate the intestinal type 2 immune response by activating downstream ILC2 and Th2 cells and repair gut barrier upon invasion of parasitic helminths, bacteria, protozoans, and enteritis through different chemo-sensing receptors, such as bitter taste receptors. Berberine is a widely used in the treatment of diarrhea in clinic, however the mechanism underlying this effect is not clear. In this study, we aim to explore the relationship between berberine and tuft cells in dextran sulfate sodium (DSS) -induced colitis.

Results: Our data showed that berberine significantly ameliorated DSS-induced colitis and regulating type 2 innate immune lymphocytes (ILC2) and Th2 immune cells via tuft cells in the gut. Furthermore, the effect of berberine on colitis was partially abolished by U73122, a bitter taste receptor inhibitor, suggesting that bitter taste signalling pathway played an important role in the effect of berberine on relieving colitis.

Conclusions: Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. Our study reveals the unique pharmacological mechanisms of berberine in the context of colitis, laying the foundation for further clinical applications of this compound.

背景:炎症性肠病(IBD)是一种以肠道免疫功能受损为特征的持续性胃肠道疾病。已有研究表明,当寄生蠕虫、细菌、原生动物、肠炎入侵时,簇状细胞可通过不同的化学感应受体(如苦味受体)激活下游的ILC2和Th2细胞,调节肠道2型免疫反应,修复肠道屏障。小檗碱在临床上广泛用于治疗腹泻,但其作用机制尚不清楚。在这项研究中,我们旨在探讨小檗碱与簇状细胞在葡聚糖硫酸钠(DSS)诱导的结肠炎中的关系。结果:我们的数据显示,小檗碱可显著改善dss诱导的结肠炎,并通过肠道簇状细胞调节2型先天免疫淋巴细胞(ILC2)和Th2免疫细胞。此外,小檗碱对结肠炎的作用被苦味受体抑制剂U73122部分消除,提示苦味信号通路在小檗碱缓解结肠炎的作用中发挥了重要作用。结论:小檗碱通过簇状细胞和苦味信号通路改善葡聚糖硫酸钠诱导的结肠炎。我们的研究揭示了小檗碱在结肠炎中的独特药理机制,为该化合物的进一步临床应用奠定了基础。
{"title":"Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling.","authors":"Yuxuan Yang, Wenqing Li, Kaineng Sun, Siyu Sun, Yong Zhang, Lin Chen, Yangyue Ni, Min Hou, Zhipeng Xu, Lu Chen, Minjun Ji","doi":"10.1186/s12915-024-02078-7","DOIUrl":"https://doi.org/10.1186/s12915-024-02078-7","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD), a persistent gastrointestinal disease, is featured with impaired gut immunity. Previous studies have demonstrated that tuft cells can regulate the intestinal type 2 immune response by activating downstream ILC2 and Th2 cells and repair gut barrier upon invasion of parasitic helminths, bacteria, protozoans, and enteritis through different chemo-sensing receptors, such as bitter taste receptors. Berberine is a widely used in the treatment of diarrhea in clinic, however the mechanism underlying this effect is not clear. In this study, we aim to explore the relationship between berberine and tuft cells in dextran sulfate sodium (DSS) -induced colitis.</p><p><strong>Results: </strong>Our data showed that berberine significantly ameliorated DSS-induced colitis and regulating type 2 innate immune lymphocytes (ILC2) and Th2 immune cells via tuft cells in the gut. Furthermore, the effect of berberine on colitis was partially abolished by U73122, a bitter taste receptor inhibitor, suggesting that bitter taste signalling pathway played an important role in the effect of berberine on relieving colitis.</p><p><strong>Conclusions: </strong>Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. Our study reveals the unique pharmacological mechanisms of berberine in the context of colitis, laying the foundation for further clinical applications of this compound.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"280"},"PeriodicalIF":4.4,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca2+ channel may modulate its β-adrenergic regulation. PKA催化亚基与心脏Ca2+通道c端结构域的三方相互作用可能调节其β-肾上腺素能调节。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-28 DOI: 10.1186/s12915-024-02076-9
Shimrit Oz, Tal Keren-Raifman, Tom Sharon, Suraj Subramaniam, Tamara Pallien, Moshe Katz, Vladimir Tsemakhovich, Anastasiia Sholokh, Baraa Watad, Debi Ranjan Tripathy, Giorgia Sasson, Orna Chomsky-Hecht, Leonid Vysochek, Maike Schulz-Christian, Claudia Fecher-Trost, Kerstin Zühlke, Daniela Bertinetti, Friedrich W Herberg, Veit Flockerzi, Joel A Hirsch, Enno Klussmann, Sharon Weiss, Nathan Dascal

Background: The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear.

Results: We show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte.

Conclusions: We discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes.

背景:β-肾上腺素能通过增加l型电压门控CaV1.2通道的电导率来增强心脏收缩,具有重要的生理和病理生理意义。刺激β-肾上腺素能受体(βAR)通过分离调节(PKAR)和催化(PKAC)亚基激活蛋白激酶A (PKA)。游离ppkac磷酸化抑制蛋白Rad,导致Ca2+内流增加。在心肌细胞中,CaV1.2的核心亚基CaV1.2α1以全长或截短(缺少远端c端(dCT))两种形式存在。信号传导效率被认为来自于多分子复合物内的蛋白质相互作用,例如通过a激酶锚定蛋白(AKAPs)将PKA(通过PKAR)锚定到CaV1.2α1。然而,在异种模型中,akap对CaV1.2的βAR调节并不重要,它们在心肌细胞中的作用也尚不清楚。结果:我们发现PKAC在心脏和异种模型中与CaV1.2α1相互作用,独立于Rad, PKAR或AKAPs。通过肽阵列分析和纯化的重组蛋白的研究表明,PKAC与CaV1.2α1-CT中的两个结构域直接结合:近端和远端c端调控结构域(PCRD和DCRD),它们也相互作用。数据表明PCRD和DCRD与ppkac既存在部分竞争,也可能同时相互作用。在异源模型非洲爪蟾卵母细胞中,缺乏dCT的CaV1.2α1的βAR调节(包含DCRD)被保留,但略有改变。结论:我们发现了PKAC与CaV1.2α1的两个结构域之间的直接相互作用。我们提出,这些三方相互作用,如果存在于体内,可能参与组织多分子信号复合物和微调心肌细胞中的βAR效应。
{"title":"Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca<sup>2+</sup> channel may modulate its β-adrenergic regulation.","authors":"Shimrit Oz, Tal Keren-Raifman, Tom Sharon, Suraj Subramaniam, Tamara Pallien, Moshe Katz, Vladimir Tsemakhovich, Anastasiia Sholokh, Baraa Watad, Debi Ranjan Tripathy, Giorgia Sasson, Orna Chomsky-Hecht, Leonid Vysochek, Maike Schulz-Christian, Claudia Fecher-Trost, Kerstin Zühlke, Daniela Bertinetti, Friedrich W Herberg, Veit Flockerzi, Joel A Hirsch, Enno Klussmann, Sharon Weiss, Nathan Dascal","doi":"10.1186/s12915-024-02076-9","DOIUrl":"10.1186/s12915-024-02076-9","url":null,"abstract":"<p><strong>Background: </strong>The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated Ca<sub>V</sub>1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca<sup>2+</sup> influx. In cardiomyocytes, the core subunit of Ca<sub>V</sub>1.2, Ca<sub>V</sub>1.2α<sub>1</sub>, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to Ca<sub>V</sub>1.2α<sub>1</sub> by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of Ca<sub>V</sub>1.2 in heterologous models, and their role in cardiomyocytes also remains unclear.</p><p><strong>Results: </strong>We show that PKAC interacts with Ca<sub>V</sub>1.2α<sub>1</sub> in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in Ca<sub>V</sub>1.2α<sub>1</sub>-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of Ca<sub>V</sub>1.2α<sub>1</sub> lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte.</p><p><strong>Conclusions: </strong>We discover direct interactions between PKAC and two domains in Ca<sub>V</sub>1.2α<sub>1</sub>. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"276"},"PeriodicalIF":4.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The neglected burden of chronic hypoxia on the resistance of glioblastoma multiforme to first-line therapies. 慢性缺氧对多形性胶质母细胞瘤一线治疗耐药性的影响。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-28 DOI: 10.1186/s12915-024-02075-w
Jolie Bou-Gharios, Georges Noël, Hélène Burckel

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.

多形性胶质母细胞瘤(GBM)是成人最常见的原发性脑肿瘤。标准治疗包括最大手术后放疗和伴随化疗与替莫唑胺(TMZ),除了辅助TMZ。然而,GBM在诊断后1-2年内的复发率仍然较高,这与GBM的异质性、基因组不稳定性、血管生成、慢性肿瘤缺氧等多种因素的积累有关。肿瘤缺氧激活下游信号通路,参与GBM适应新的缺氧环境,从而导致抵抗和复发现象,尽管采用了多模式治疗方法来根除肿瘤。因此,在这篇综述中,我们将通过遗传和表观遗传修饰来关注慢性或有限弥漫性缺氧在肿瘤持久性中的发展及其意义。然后,我们将详细介绍缺氧诱导的重要生物途径和机制的激活,这些途径和机制有助于GBM抵抗。最后,我们将讨论基于蛋白质组学的方法,以鼓励基于缺氧特征的个性化GBM治疗的含义。
{"title":"The neglected burden of chronic hypoxia on the resistance of glioblastoma multiforme to first-line therapies.","authors":"Jolie Bou-Gharios, Georges Noël, Hélène Burckel","doi":"10.1186/s12915-024-02075-w","DOIUrl":"10.1186/s12915-024-02075-w","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"278"},"PeriodicalIF":4.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Whole-genome DNA methylomes of tree shrew brains reveal conserved and divergent roles of DNA methylation on sex chromosome regulation. 树鼩全基因组DNA甲基化组揭示了DNA甲基化在性染色体调控中的保守性和差异性作用。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-28 DOI: 10.1186/s12915-024-02071-0
Dongmin R Son, Yifan Kong, Yulian Tan, Ting Hu, Lei Shi, Soojin V Yi

Background: The tree shrew (Tupaia belangeri) is a promising emerging model organism in biomedical studies, notably due to their evolutionary proximity to primates. To enhance our understanding of how DNA methylation is implicated in regulation of gene expression and the X chromosome inactivation (XCI) in tree shrew brains, here we present their first genome-wide, single-base-resolution methylomes integrated with transcriptomes from prefrontal cortices.

Results: Genome-wide relationships between DNA methylation and gene expression are consistent with those in other mammals. Interestingly, we observed a clear and significant global reduction (hypomethylation) of DNA methylation across the entire female X chromosome compared to male X. Female hypomethylation does not directly contribute to the gene silencing of the inactivated X chromosome nor does it significantly drive sex-specific gene expression in tree shrews. However, we identified a putative regulatory region in the 5' end of the X-inactive-specific transcript (Xist) gene, whose pattern of differential DNA methylation strongly relate to its sex-differential expression in tree shrews. Furthermore, differential methylation of this region is conserved across different species. We also provide evidence suggesting that the observed difference between human and tree shrew X-linked promoter methylation is associated with the difference in genomic CpG contents.

Conclusions: Our study offers novel information on genomic DNA methylation of tree shrews as well as insights into the evolution of sex chromosome regulation in mammals. Specifically, we show conserved role of DNA methylation in regulation of Xist expression and propose genomic CpG contents as a factor in driving sex-differential DNA methylation of X-linked promoters.

背景:树鼩(Tupaia belangeri)在生物医学研究中是一种很有前途的新兴模式生物,特别是由于它们与灵长类动物的进化接近。为了加强我们对树鼩大脑中DNA甲基化如何参与基因表达调控和X染色体失活(XCI)的理解,我们在这里展示了他们的第一个全基因组、单碱基分辨率的甲基组与来自前额叶皮层的转录组的整合。结果:DNA甲基化与基因表达的全基因组关系与其他哺乳动物一致。有趣的是,与雄性X染色体相比,我们观察到整个雌性X染色体DNA甲基化的明显和显著的整体减少(低甲基化)。雌性低甲基化并不直接导致失活X染色体的基因沉默,也不会显著推动树鼩性别特异性基因的表达。然而,我们在x无活性特异性转录本(Xist)基因的5'端发现了一个假定的调控区域,其差异DNA甲基化模式与其在树鼩中的性别差异表达密切相关。此外,该区域的甲基化差异在不同物种之间是保守的。我们还提供证据表明,人类和树鼩x连锁启动子甲基化的差异与基因组CpG含量的差异有关。结论:我们的研究为树鼩基因组DNA甲基化提供了新的信息,并为哺乳动物性染色体调控的进化提供了新的见解。具体来说,我们发现DNA甲基化在Xist表达调控中的保守作用,并提出基因组CpG含量是驱动x连锁启动子性别差异DNA甲基化的一个因素。
{"title":"Whole-genome DNA methylomes of tree shrew brains reveal conserved and divergent roles of DNA methylation on sex chromosome regulation.","authors":"Dongmin R Son, Yifan Kong, Yulian Tan, Ting Hu, Lei Shi, Soojin V Yi","doi":"10.1186/s12915-024-02071-0","DOIUrl":"10.1186/s12915-024-02071-0","url":null,"abstract":"<p><strong>Background: </strong>The tree shrew (Tupaia belangeri) is a promising emerging model organism in biomedical studies, notably due to their evolutionary proximity to primates. To enhance our understanding of how DNA methylation is implicated in regulation of gene expression and the X chromosome inactivation (XCI) in tree shrew brains, here we present their first genome-wide, single-base-resolution methylomes integrated with transcriptomes from prefrontal cortices.</p><p><strong>Results: </strong>Genome-wide relationships between DNA methylation and gene expression are consistent with those in other mammals. Interestingly, we observed a clear and significant global reduction (hypomethylation) of DNA methylation across the entire female X chromosome compared to male X. Female hypomethylation does not directly contribute to the gene silencing of the inactivated X chromosome nor does it significantly drive sex-specific gene expression in tree shrews. However, we identified a putative regulatory region in the 5' end of the X-inactive-specific transcript (Xist) gene, whose pattern of differential DNA methylation strongly relate to its sex-differential expression in tree shrews. Furthermore, differential methylation of this region is conserved across different species. We also provide evidence suggesting that the observed difference between human and tree shrew X-linked promoter methylation is associated with the difference in genomic CpG contents.</p><p><strong>Conclusions: </strong>Our study offers novel information on genomic DNA methylation of tree shrews as well as insights into the evolution of sex chromosome regulation in mammals. Specifically, we show conserved role of DNA methylation in regulation of Xist expression and propose genomic CpG contents as a factor in driving sex-differential DNA methylation of X-linked promoters.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"277"},"PeriodicalIF":4.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multiple losses of aKRAB from PRDM9 coincide with a teleost-specific intron size distribution. PRDM9 中 aKRAB 的多次缺失与远足鱼特有的内含子大小分布相吻合。
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-27 DOI: 10.1186/s12915-024-02059-w
Ann-Christin Zinner, Lars Martin Jakt

Background: Primary transcripts are largely comprised of intronic sequences that are excised and discarded shortly after synthesis. In vertebrates, the shape of the intron size distribution is largely constant; however, most teleost fish have a diverged log-bimodal 'teleost distribution' (TD) that is seen only in teleosts. How the TD evolved and to what extent this was affected by adaptative or non-adaptive mechanisms is unknown.

Results: Here, we show that the TD has evolved independently at least six times and that its appearance is linked to the loss of the aKRAB domain from PRDM9. We determined intron size distributions and identified PRDM9 orthologues from annotated genomes in addition to scanning 1193 teleost assemblies for the aKRAB domain. We show that a diverged form of PRDM9 ( β ) is predominant in teleosts whereas the α version is absent from most species. Only a subset of PRDM9- α proteins contain aKRAB, and hence, it is present only in a small number of teleost lineages. Almost all lineages lacking aKRAB (but no species with) had TDs.

Conclusions: In mammals, PRDM9 defines the sites of meiotic recombination through a mechanism that increases structural variance and depends on aKRAB. The loss of aKRAB is likely to have shifted the locations of both recombination and structural variance hotspots. Our observations suggest that the TD evolved as a side-effect of these changes and link recombination to the evolution of intron size illustrating how genome architectures can evolve in the absence of selection.

背景:初级转录本主要由内含子序列组成,这些序列在合成后不久就会被切除和丢弃。在脊椎动物中,内含子大小分布的形状基本上是恒定的;然而,大多数远洋鱼类具有仅见于远洋鱼类的对数双峰分布(TD)。TD是如何进化的,在多大程度上受到适应性或非适应性机制的影响,这些都是未知的:结果:在此,我们发现 TD 已独立进化了至少六次,其出现与 PRDM9 中 aKRAB 结构域的缺失有关。我们确定了内含子的大小分布,并从已注释的基因组中确定了 PRDM9 的同源物,此外还扫描了 1193 个远缘动物基因组以寻找 aKRAB 结构域。我们发现,PRDM9的分化形式(β)在远足类动物中占主导地位,而α版本在大多数物种中都不存在。只有一小部分 PRDM9-α 蛋白含有 aKRAB,因此它只存在于少数远足类动物中。几乎所有缺乏 aKRAB 的物种(但没有物种含有 aKRAB)都有 TDs:结论:在哺乳动物中,PRDM9通过一种增加结构变异并依赖于aKRAB的机制确定减数分裂重组的位点。aKRAB的缺失很可能改变了重组和结构变异热点的位置。我们的观察结果表明,TD的进化是这些变化的副作用,并将重组与内含子大小的进化联系起来,说明了基因组结构是如何在没有选择的情况下进化的。
{"title":"Multiple losses of aKRAB from PRDM9 coincide with a teleost-specific intron size distribution.","authors":"Ann-Christin Zinner, Lars Martin Jakt","doi":"10.1186/s12915-024-02059-w","DOIUrl":"10.1186/s12915-024-02059-w","url":null,"abstract":"<p><strong>Background: </strong>Primary transcripts are largely comprised of intronic sequences that are excised and discarded shortly after synthesis. In vertebrates, the shape of the intron size distribution is largely constant; however, most teleost fish have a diverged log-bimodal 'teleost distribution' (TD) that is seen only in teleosts. How the TD evolved and to what extent this was affected by adaptative or non-adaptive mechanisms is unknown.</p><p><strong>Results: </strong>Here, we show that the TD has evolved independently at least six times and that its appearance is linked to the loss of the aKRAB domain from PRDM9. We determined intron size distributions and identified PRDM9 orthologues from annotated genomes in addition to scanning 1193 teleost assemblies for the aKRAB domain. We show that a diverged form of PRDM9 ( <math><mi>β</mi></math> ) is predominant in teleosts whereas the <math><mi>α</mi></math> version is absent from most species. Only a subset of PRDM9- <math><mi>α</mi></math> proteins contain aKRAB, and hence, it is present only in a small number of teleost lineages. Almost all lineages lacking aKRAB (but no species with) had TDs.</p><p><strong>Conclusions: </strong>In mammals, PRDM9 defines the sites of meiotic recombination through a mechanism that increases structural variance and depends on aKRAB. The loss of aKRAB is likely to have shifted the locations of both recombination and structural variance hotspots. Our observations suggest that the TD evolved as a side-effect of these changes and link recombination to the evolution of intron size illustrating how genome architectures can evolve in the absence of selection.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"275"},"PeriodicalIF":4.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11600626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A novel human protein-coding locus identified using a targeted RNA enrichment technique. 利用靶向 RNA 富集技术发现的新型人类蛋白质编码基因座
IF 4.4 1区 生物学 Q1 BIOLOGY Pub Date : 2024-11-26 DOI: 10.1186/s12915-024-02069-8
Lu Tang, Dongyang Xu, Lingcong Luo, Weiyan Ma, Xiaojie He, Yong Diao, Rongqin Ke, Philipp Kapranov

Background: Accurate and comprehensive genomic annotation, including the full list of protein-coding genes, is vital for understanding the molecular mechanisms of human biology. We have previously shown that the genome contains a multitude of yet hidden functional exons and transcripts, some of which might represent novel mRNAs. These results resonate with those from other groups and strongly argue that two decades after the completion of the first draft of the human genome sequence, the current annotation of human genes and transcripts remains far from being complete.

Results: Using a targeted RNA enrichment technique, we showed that one of the novel functional exons previously discovered by us and currently annotated as part of a long non-coding RNA, is actually a part of a novel protein-coding gene, InSETG-4, which encodes a novel human protein with no known homologs or motifs. We found that InSETG-4 is induced by various DNA-damaging agents across multiple cell types and therefore might represent a novel component of DNA damage response. Despite its low abundance in bulk cell populations, InSETG-4 exhibited expression restricted to a small fraction of cells, as demonstrated by the amplification-based single-molecule fluorescence in situ hybridization (asmFISH) analysis.

Conclusions: This study argues that yet undiscovered human protein-coding genes exist and provides an example of how targeted RNA enrichment techniques can help to fill this major gap in our knowledge of the information encoded in the human genome.

背景:准确而全面的基因组注释(包括完整的蛋白质编码基因列表)对于了解人类生物学的分子机制至关重要。我们之前已经证明,基因组包含大量尚未被发现的功能外显子和转录本,其中一些可能代表新型 mRNA。这些结果与其他研究小组的结果产生了共鸣,并有力地证明了在人类基因组序列初稿完成二十年后,目前对人类基因和转录本的注释仍远未完成:我们利用靶向 RNA 富集技术发现,我们之前发现的、目前被注释为长非编码 RNA 的一部分的新型功能外显子之一,实际上是一个新型蛋白质编码基因 InSETG-4 的一部分,该基因编码一种新型人类蛋白质,没有已知的同源物或主题。我们发现,InSETG-4 会被多种细胞类型中的各种 DNA 损伤因子诱导,因此可能是 DNA 损伤反应的一个新成分。基于扩增的单分子荧光原位杂交(asmFISH)分析表明,尽管InSETG-4在大量细胞中的丰度较低,但它的表达仅限于一小部分细胞:这项研究证明,人类还存在未被发现的蛋白质编码基因,并提供了一个实例,说明靶向 RNA 富集技术如何有助于填补我们对人类基因组编码信息了解的这一重大空白。
{"title":"A novel human protein-coding locus identified using a targeted RNA enrichment technique.","authors":"Lu Tang, Dongyang Xu, Lingcong Luo, Weiyan Ma, Xiaojie He, Yong Diao, Rongqin Ke, Philipp Kapranov","doi":"10.1186/s12915-024-02069-8","DOIUrl":"10.1186/s12915-024-02069-8","url":null,"abstract":"<p><strong>Background: </strong>Accurate and comprehensive genomic annotation, including the full list of protein-coding genes, is vital for understanding the molecular mechanisms of human biology. We have previously shown that the genome contains a multitude of yet hidden functional exons and transcripts, some of which might represent novel mRNAs. These results resonate with those from other groups and strongly argue that two decades after the completion of the first draft of the human genome sequence, the current annotation of human genes and transcripts remains far from being complete.</p><p><strong>Results: </strong>Using a targeted RNA enrichment technique, we showed that one of the novel functional exons previously discovered by us and currently annotated as part of a long non-coding RNA, is actually a part of a novel protein-coding gene, InSETG-4, which encodes a novel human protein with no known homologs or motifs. We found that InSETG-4 is induced by various DNA-damaging agents across multiple cell types and therefore might represent a novel component of DNA damage response. Despite its low abundance in bulk cell populations, InSETG-4 exhibited expression restricted to a small fraction of cells, as demonstrated by the amplification-based single-molecule fluorescence in situ hybridization (asmFISH) analysis.</p><p><strong>Conclusions: </strong>This study argues that yet undiscovered human protein-coding genes exist and provides an example of how targeted RNA enrichment techniques can help to fill this major gap in our knowledge of the information encoded in the human genome.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"22 1","pages":"273"},"PeriodicalIF":4.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
BMC Biology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1