Pub Date : 2024-12-05DOI: 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.
{"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}
Pub Date : 2024-12-03DOI: 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.
{"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}
Pub Date : 2024-12-03DOI: 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.
{"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}
Pub Date : 2024-12-02DOI: 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.
{"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}
Pub Date : 2024-12-02DOI: 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.
{"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}
Pub Date : 2024-11-28DOI: 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.
{"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}
Pub Date : 2024-11-28DOI: 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.
{"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}
Pub Date : 2024-11-28DOI: 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.
{"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}
Pub Date : 2024-11-27DOI: 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 ( ) is predominant in teleosts whereas the version is absent from most species. Only a subset of PRDM9- 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.
{"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}
Pub Date : 2024-11-26DOI: 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}