Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献_第4页

Specific DNA features of the RNA polymerase I core promoter element targeted by core factor 核心因子所针对的 RNA 聚合酶 I 核心启动子元件的特定 DNA 特征

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-04-09 DOI: 10.1016/j.bbagrm.2025.195088

Nathan J. Munoff, Brian J. Zeberl, Matthew A. Palmer, Wayne A. Decatur, Bridget M. Walker, Jyoti D. Adala, Zsuzsa K. Szemere, Aula M. Fakhouri, Bruce A. Knutson

RNA polymerase I (Pol I) is essential for ribosomal RNA (rRNA) synthesis, driving ribosome biogenesis in eukaryotes. Transcription initiation by Pol I requires core factor (CF) binding to the core element (CE) of the ribosomal DNA (rDNA) promoter. Despite structural conservation across species, significant sequence variability suggests CF recognizes DNA through structural features rather than specific sequences. We investigated CF's DNA binding preferences to elucidate the role of DNA structural properties in CE recognition. Analysis of CE sequences from 35 fungal species revealed conserved structural features, notably a rigid AT-rich patch at positions −22 to −20 and a conserved G base pair at position −24. Competition-based electrophoretic mobility shift assays (EMSA) with single base-pair substitutions showed CF tolerates mutations at many positions but is sensitive to changes in the AT-rich patch. Loss of CF binding correlated with alterations in DNA structural properties such as increased bendability, decreased curvature, widened minor groove width, and altered helix twist. In vitro SELEX experiments identified novel CE sequences preferentially bound by CF, exhibiting increased GC content, higher bendability, and decreased curvature despite lacking sequence conservation. Classification based on bendability profiles revealed CF preferentially binds bendable sequences. In vivo selection assays confirmed these findings, demonstrating consistent CF binding preferences within a cellular context. Our results indicate that CF recognizes and binds to the CE primarily through specific DNA structural features rather than nucleotide sequences. Structural properties like bendability, curvature, and minor groove width are critical determinants of CF binding, facilitating effective Pol I transcription initiation.

RNA聚合酶I （Pol I）是真核生物中核糖体RNA （rRNA）合成和驱动核糖体生物发生所必需的。Pol I的转录起始需要核心因子（CF）与核糖体DNA （rDNA）启动子的核心元件（CE）结合。尽管物种之间存在结构守恒，但显著的序列差异表明CF通过结构特征而不是特定序列识别DNA。我们研究了CF的DNA结合偏好，以阐明DNA结构特性在CE识别中的作用。对35种真菌CE序列的分析显示，CE序列具有保守的结构特征，特别是在- 22 ~ - 20位置有一个刚性的at -rich patch，在- 24位置有一个保守的G碱基对。采用单碱基对替换的基于竞争的电泳迁移迁移试验（EMSA）显示，CF可以耐受许多位置的突变，但对富含at的斑块的变化敏感。CF结合的丧失与DNA结构特性的改变相关，如可弯曲性增加、曲率降低、小凹槽宽度变宽和螺旋扭曲改变。体外SELEX实验发现，新的CE序列优先与CF结合，尽管缺乏序列保守性，但GC含量增加，可弯曲性提高，曲率降低。基于可弯曲性特征的分类显示，CF优先结合可弯曲序列。体内选择分析证实了这些发现，证明了在细胞背景下一致的CF结合偏好。我们的研究结果表明，CF主要通过特定的DNA结构特征而不是核苷酸序列来识别和结合CE。结构特性，如可弯曲性，曲率和小凹槽宽度是CF结合的关键决定因素，促进有效的Pol I转录起始。

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引用次数: 0

Hypoxia inducible factor HIF1α elevates expression of mRNA capping enzyme during cobalt chloride-induced hypoxia 缺氧诱导因子HIF1α在氯化钴诱导的缺氧过程中升高mRNA capping酶的表达。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-04-05 DOI: 10.1016/j.bbagrm.2025.195087

Safirul Islam, Chandrama Mukherjee

In response to hypoxia, hypoxia-inducible factors (HIFs) control the transcriptomic output to mitigate the hypoxic stress. Long noncoding RNAs (lncRNA) are found to be very crucial in regulating hypoxia. Like mRNAs, lncRNAs are protected by 5′ caps that are added by mRNA capping enzyme (CE) in the nucleus. The previous concept that capping takes place in the nucleus was changed by the recognition of a cytoplasmic pool of capping enzyme (cCE). cCE has been shown to recap its substrate uncapped mRNAs or long noncoding RNAs (lncRNAs) present in the cytoplasm, preventing their degradation, even during arsenite-induced oxidative stress. In this study, we examined the effect of CoCl₂ induced hypoxia on cCE and its function in regulating the substrate lncRNAs.

Here, we show that CoCl₂ induced hypoxia elevates the expressions of nuclear and cytoplasmic CE in HIF1α dependent manner as evidenced by Chromatin immunoprecipitation and HIF1α inhibitor experiments. Furthermore, we found cCE post-transcriptionally controls the stability of its target lncRNAs amidst CoCl₂ induced hypoxia. These results suggest that cCE, upregulated by HIF1α, may act as a posttranscriptional modulator for a few cCE-targeted lncRNAs.

低氧诱导因子（hif）通过调控转录组输出来缓解低氧胁迫。长链非编码rna （Long noncoding rna, lncRNA）在缺氧调控中起着至关重要的作用。与mRNA一样，lncRNAs受到细胞核中mRNA capping酶（CE）添加的5'帽的保护。由于认识到胞质盖顶酶（cCE）的存在，以前认为盖顶发生在细胞核内的观念发生了改变。研究表明，cCE可以重新封装存在于细胞质中的底物无帽mrna或长链非编码rna (lncRNAs)，即使在亚砷酸盐诱导的氧化应激过程中也能阻止它们的降解。在本研究中，我们研究了CoCl2诱导的缺氧对cCE的影响及其在调节底物lncrna中的功能。在这里，我们通过染色质免疫沉淀和HIF1α抑制剂实验证明，CoCl2诱导的缺氧以依赖于HIF1α的方式提高细胞核和细胞质CE的表达。此外，我们发现cCE通过转录后调控其靶lncrna在CoCl2诱导的缺氧中的稳定性。这些结果表明，hif - 1α上调的cCE可能作为一些靶向cCE的lncrna的转录后调节剂。

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引用次数: 0

Transcription factors associated with regulation of transcriptome in human thigh and calf muscles at baseline and after six days of disuse 在基线和停用6天后，与人大腿和小腿肌肉转录组调节相关的转录因子。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-02-19 DOI: 10.1016/j.bbagrm.2025.195086

Anna A. Borzykh , Pavel A. Makhnovskii , Ivan I. Ponomarev, Tatiana F. Vepkhvadze, Egor M. Lednev, Ilya V. Rukavishnikov, Oleg I. Orlov, Elena S. Tomilovskaya, Daniil V. Popov

Disuse has a negative impact on the postural muscles of the trunk and legs. Different leg muscles demonstrate a differentiated and conservative response to disuse, in terms of a decrease in muscle mass, strength, aerobic performance, and changes in gene expression. We aimed to identify transcription factors regulating gene expression at baseline and after disuse in human m. soleus – a “slow” muscle with a strong postural function, and “mixed” m. vastus lateralis. Biopsies were taken from these muscles prior to and after 6 days of strict disuse (dry immersion). The enriched transcription factor binding sites (and corresponding factors) in the individual promoter regions of co-expressed genes were examined using the positional weight matrix approach. The baseline transcriptomic profiles and the disuse-induced changes (RNA-seq) differ significantly between muscles. In particular, the specific and significant response to disuse in m. soleus was found to be strongly related to the suppression of genes regulating the mitochondrial energy metabolism, the activation of the inflammatory response and the ubiquitin-proteasome system. This response is associated with the proinflammatory transcription factors such as families IRF, STAT, and other. The validity of approximately two-thirds of the predicted transcription factors was indirectly confirmed by the analysis of their function described in the literature. These identified transcription factors appear to be promising candidates for future targeted studies that mechanistically investigate gene expression regulation in various muscles at baseline, following disuse or inactivity.

不使用对躯干和腿部的姿势肌肉有负面影响。在肌肉质量、力量、有氧运动表现和基因表达变化方面，不同的腿部肌肉表现出不同的和保守的废用反应。我们的目的是确定在人类比目鱼肌（一种具有强大姿势功能的“慢”肌肉）和“混合”股外侧肌中基线和废用后调节基因表达的转录因子。在严格弃用（干浸泡）之前和之后6 天，对这些肌肉进行活组织检查。利用位置权重矩阵法检测共表达基因的单个启动子区域中富集的转录因子结合位点（和相应的因子）。基线转录组谱和废用诱导的变化（RNA-seq）在肌肉之间有显著差异。特别是，比目鱼对废用的特异性和显著反应被发现与调节线粒体能量代谢的基因的抑制、炎症反应的激活和泛素-蛋白酶体系统的激活密切相关。这种反应与促炎转录因子如家族IRF、STAT等有关。大约三分之二的预测转录因子的有效性通过文献中描述的功能分析间接证实。这些已确定的转录因子似乎是未来有针对性的研究的有希望的候选者，这些研究将在基线、不使用或不活动后对各种肌肉的基因表达调控进行机制研究。

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引用次数: 0

UPS regulation of gene expression and genome integrity UPS对基因表达和基因组完整性的调控。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-01-30 DOI: 10.1016/j.bbagrm.2025.195078

Sukesh R. Bhaumik

引用次数: 0

TAP-MS analysis of FACT interactions and regulation by a ubiquitin ligase, San1 泛素连接酶San1对FACT相互作用及调控的TAP-MS分析。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-01-22 DOI: 10.1016/j.bbagrm.2025.195077

Priyanka Barman, Pritam Chakraborty, Shalini Guha, Amala Kaja, Rhea Bhaumik, Sukesh R. Bhaumik

An evolutionarily conserved heterodimeric FACT (Facilitates chromatin transcription) regulates transcription, DNA repair, replication and other cellular processes via its interactions with other proteins. FACT is recently found to be regulated via ubiquitylation and 26S proteasomal degradation, alteration of which is associated with aberrant transcription and genome integrity. However, there has not been a systematic study to analyze FACT interactions proteome-wide in the presence and absence of its UPS (Ubiquitin-proteasome system) regulation, which could reveal new FACT interactors with mechanistic and functional implications. Here, we have adopted a proteome-wide approach via TAP (Tandem affinity purification)-mediated pull-down of FACT and its interactors from the soluble and insoluble cellular fractions followed by MS (Mass-spectrometry) analysis. We find distinct interactors of FACT in the soluble and insoluble fractions in addition to a common set in both. While a set of all these interactors overlaps with previously known FACT partners, many are new, which are involved in different cellular processes such as transcription, DNA repair and chromatin regulation. Further, an intrinsically disordered ubiquitin ligase, San1, that ubiquitylates the Spt16 component of FACT for proteasomal degradation to regulate chromatin, transcription and genome integrity is found to influence the interactions of FACT with a set of proteins including epigenetic, transcription and DNA repair factors. Collectively, our results unveil proteome-wide FACT interactions and regulation by a ubiquitin ligase, hence shedding much light on FACT networks with functional and mechanistic implications.

一种进化保守的异源二聚体 FACT（促进染色质转录）通过与其他蛋白质的相互作用调节转录、DNA 修复、复制和其他细胞过程。最近发现 FACT 可通过泛素化和 26S 蛋白质体降解进行调控，而泛素化和 26S 蛋白质体降解的改变与转录异常和基因组完整性有关。然而，目前还没有系统的研究来分析在存在和不存在 UPS（泛素-蛋白酶体系统）调控的情况下 FACT 与整个蛋白体的相互作用，这可能会揭示出具有机制和功能意义的新的 FACT 相互作用因子。在这里，我们采用了一种全蛋白质组的方法，通过串联亲和纯化（TAP）介导，从可溶性和非可溶性细胞组分中提取 FACT 及其相互作用物，然后进行质谱分析。我们在可溶性和不可溶性馏分中发现了不同的 FACT 相互作用体，此外还在两者中发现了一组共同的相互作用体。所有这些相互作用者中有一部分与以前已知的 FACT 伙伴重叠，但也有许多是新的，它们参与了转录、DNA 修复和染色质调控等不同的细胞过程。此外，我们还发现了一种内在无序泛素连接酶 San1，它能泛素化 FACT 的 Spt16 成分，使其蛋白酶体降解，从而调节染色质、转录和基因组的完整性。总之，我们的研究结果揭示了整个蛋白质组的 FACT 相互作用以及泛素连接酶的调控，从而揭示了 FACT 网络的功能和机理。

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引用次数: 0

Susceptibility to pseudoexfoliation linked to intronic variant rs4926246 in CACNA1A: Evidence from an Indian population study CACNA1A基因内含子变异rs4926246对假脱落的易感性：来自印度人群研究的证据

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-01-16 DOI: 10.1016/j.bbagrm.2025.195076

Bushra Hayat , Swagatika Panigrahi , Senjit Ram Behera , Pranjya Paramita Mohanty , Debasmita Pankaj Alone

Pseudoexfoliation (PEX) is an age-related, complex systemic disorder of protein aggregopathy. It is characterized by the extracellular fibril depositions, termed PEX fibrils, initially observed in various organ tissues during pseudoexfoliation syndrome (PEXS) and with significant prominence in the eye during advanced pseudoexfoliation glaucoma (PEXG). The study explores the association between CACNA1A (calcium channel, voltage-dependent, P/Q type, alpha 1 A subunit) variants and PEX in an Indian population. The investigation involved genotyping one intronic single nucleotide polymorphism (SNP), rs4926244, and three tag SNPs using the Sanger and TaqMan genotyping approaches in a cohort of 300 controls and 300 PEX patients (including 200 PEXS and 100 PEXG cases). Findings from the present study revealed a significant association at both allelic and genotypic levels for rs4926246, whereas rs4926244 showed association only at the genotypic level with PEX. Functional assays demonstrated increased mRNA expression linked to the risk genotype of both variants and luciferase reporter assays indicated an allele-specific regulatory effect of rs4926246.While in silico analysis predicted potential transcription factor binding sites for c-Myc and Hypoxia-inducing factor-1 (HIF-1) at the rs4926246 locus, electrophoretic mobility shift assay (EMSA) validated that only the “T” variant showed the reduced binding affinity with c-Myc compared to the protective variant “C”. Our study identifies rs4926246, an intronic variant strongly associated with both PEXS and PEXG, potentially influencing gene expression and protein binding, warranting further investigation into its role in PEX pathogenesis.

假性脱落（PEX）是一种与年龄相关的复杂的全身性蛋白质聚集性疾病。它的特征是细胞外纤维沉积，称为PEX原纤维，最初在假性脱落综合征（PEXS）期间在各种器官组织中观察到，在晚期假性脱落性青光眼（PEXG）期间在眼睛中显著突出。该研究探讨了CACNA1 A（钙通道，电压依赖性，P/Q型，α 1 A亚基）变异与印度人群PEX之间的关系。该研究使用Sanger和TaqMan基因分型方法对300名对照和300名PEX患者（包括200名PEX和100名PEX患者）的1个内含子单核苷酸多态性（SNP） rs4926244和3个标签SNP进行基因分型。本研究结果显示rs4926246在等位基因和基因型水平上均与PEX显著相关，而rs4926244仅在基因型水平上与PEX相关。功能分析显示mRNA表达增加与两种变异的风险基因型相关，荧光素酶报告基因分析显示rs4926246具有等位基因特异性调控作用。虽然硅分析预测了C - myc和缺氧诱导因子-1 （HIF-1）在rs4926246位点的潜在转录因子结合位点，但电泳迁移迁移试验（EMSA）证实，与保护性变异“C”相比，只有“T”变异显示出与C - myc的结合亲和力降低。我们的研究发现了rs4926246，这是一个与PEX和PEX密切相关的内含子变异，可能影响基因表达和蛋白质结合，值得进一步研究其在PEX发病中的作用。

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引用次数: 0

Transcriptional responses of three slc39a/zip members (zip4, zip5 and zip9) and their roles in Zn metabolism in grass carp (Ctenopharyngodon idella) slc39a/zip三个成员zip4、zip5和zip9的转录响应及其在草鱼锌代谢中的作用

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2024-12-13 DOI: 10.1016/j.bbagrm.2024.195075

Jia-Cheng Guo , Peng-Cheng Xu , Yi-Chuang Xu , Tian-Hua Zhang , Lu-Lu Liu , Tao Liu , Zhi Luo

In order to explore the regulatory mechanism of zip4, zip5 and zip9 in zinc metabolism of grass carp (Ctenopharyngodon idella), the effects of zinc (Zn) on the mRNA expression of zip4, zip5 and zip9 were investigated. Compared to the control, the mRNA levels of zip4 and zip9 were significantly reduced under low and high zinc in L8824 cells; the mRNA expression level of zip5 was significantly increased under low and high zinc incubation. Then, their promoter sequences were cloned, which were 2361 bp, 2004 bp and 2186 bp sequences for zip4, zip5 and zip9 promoters, respectively. The transcriptional activities of the three promoters had different responses to Zn treatment. The transcriptional factor signal transducer and activator of transcription 3 (STAT3) had specific binding sites at −1111/−1121 bp of zip5 promoter and at −1679/−1689 bp of zip9 promoter. Similarly, krüppel-like factor 4 (KLF4) could specifically bind to the −599/−609 bp sequence on the zip5 promoter and the −261/−272 bp sequence on the zip9 promoter. The results of electrophoretic mobility-shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) indicated that Zn incubation increased DNA binding capacity of STAT3 to zip5 and zip9 promoters, and decreased DNA binding capacity of KLF4 to zip5 and zip9 promoters. This study provides a good basis for elucidating the regulatory mechanism of zinc metabolism in the vertebrates.

为探讨zip4、zip5和zip9在草鱼锌代谢中的调控机制，研究了锌（Zn）对zip4、zip5和zip9 mRNA表达的影响。与对照相比，低锌和高锌处理下，L8824细胞中zip4和zip9的mRNA表达水平显著降低；低锌和高锌孵育下，zip5 mRNA表达量显著升高。然后克隆它们的启动子序列，zip4、zip5和zip9启动子分别为2361 bp、2004 bp和2186 bp序列。三种启动子的转录活性对锌处理有不同的响应。转录因子信号转导和转录3激活因子（STAT3）在zip5启动子的-1111/-1121 bp和zip9启动子的-1679/-1689 bp处具有特异性结合位点。类似地，kr ppel样因子4 （KLF4）可以特异性结合zip5启动子上的-599/-609 bp序列和zip9启动子上的-261/-272 bp序列。电泳迁移迁移试验（EMSA）和染色质免疫沉淀（ChIP）结果表明，锌培养提高了STAT3对zip5和zip9启动子的DNA结合能力，降低了KLF4对zip5和zip9启动子的DNA结合能力。本研究为阐明脊椎动物锌代谢的调控机制提供了良好的基础。

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引用次数: 0

Experimental approaches to investigate biophysical interactions between homeodomain transcription factors and DNA 研究同源域转录因子与DNA之间生物物理相互作用的实验方法。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2024-12-05 DOI: 10.1016/j.bbagrm.2024.195074

Fadwa Mekkaoui , Robert A. Drewell , Jacqueline M. Dresch , Donald E. Spratt

Homeodomain transcription factors (TFs) bind to specific DNA sequences to regulate the expression of target genes. Structural work has provided insight into molecular identities and aided in unraveling structural features of these TFs. However, the detailed affinity and specificity by which these TFs bind to DNA sequences is still largely unknown. Qualitative methods, such as DNA footprinting, Electrophoretic Mobility Shift Assays (EMSAs), Systematic Evolution of Ligands by Exponential Enrichment (SELEX), Bacterial One Hybrid (B1H) systems, Surface Plasmon Resonance (SPR), and Protein Binding Microarrays (PBMs) have been widely used to investigate the biochemical characteristics of TF-DNA binding events. In addition to these qualitative methods, bioinformatic approaches have also assisted in TF binding site discovery. Here we discuss the advantages and limitations of these different approaches, as well as the benefits of utilizing more quantitative approaches, such as Mechanically Induced Trapping of Molecular Interactions (MITOMI), Microscale Thermophoresis (MST) and Isothermal Titration Calorimetry (ITC), in determining the biophysical basis of binding specificity of TF-DNA complexes and improving upon existing computational approaches aimed at affinity predictions.

同源结构域转录因子（TFs）结合到特定的DNA序列来调节靶基因的表达。结构工作提供了对分子身份的深入了解，并有助于揭示这些tf的结构特征。然而，这些tf与DNA序列结合的详细亲和力和特异性在很大程度上仍然未知。定性方法，如DNA足迹、电泳迁移率转移测定（EMSAs）、配体指数富集系统进化（SELEX）、细菌一杂交（B1H）系统、表面等离子体共振（SPR）和蛋白质结合微阵列（PBMs）已被广泛用于研究TF-DNA结合事件的生化特性。除了这些定性方法外，生物信息学方法也有助于发现TF结合位点。在这里，我们讨论了这些不同方法的优点和局限性，以及利用更多定量方法的好处，如机械诱导分子相互作用捕获（MITOMI），微尺度热泳（MST）和等温滴定量热法（ITC），在确定TF-DNA复合物结合特异性的生物物理基础和改进现有的旨在亲和力预测的计算方法。

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引用次数: 0

Competing endogenous RNAs network and therapeutic implications: New horizons in disease research 竞争内源性rna网络和治疗意义：疾病研究的新视野。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2024-12-02 DOI: 10.1016/j.bbagrm.2024.195073

Nahla E. El-Ashmawy , Eman G. Khedr , Renad T. Darwish , Amera O. Ibrahim

Different diseases may arise from the dysregulation of non-coding RNAs (ncRNAs), which regulation is necessary for maintaining cellular homeostasis. ncRNAs are regulated by transcriptional, post-transcriptional, translational and post-translational processes. Post-transcriptional regulation of gene expression is carried out by microRNAs (miRNAs), a class of small ncRNA molecules, which can identify their target sites by a brief nucleotide sequence, known as the miRNA response element (MRE), present on the miRNA seed sequence and the target transcript. This binding between miRNAs and targets can regulate the gene expression through inhibition of translation or degradation of target messenger RNA (mRNA). The transcripts that share MREs can be involved in competition for the central miRNA pool, which could have an indirect impact on each other's regulation. This competition network is called competing endogenous RNAs network (ceRNET). Many ncRNAs, including circular RNA, pseudogene, and long non-coding RNA, as well as mRNA, a coding RNA transcript, make up ceRNET. These components play a crucial role in post-transcriptional regulation and are involved in the diagnosis and treatment of many pathological disorders. The mechanism of ceRNET and its essential components, as well as their therapeutic implications in different diseases such as cancer, diabetes mellitus, neurological, cardiovascular, hepatic and respiratory disorders were covered in this review.

不同的疾病可能是由非编码rna （ncRNAs）的失调引起的，而非编码rna的调节是维持细胞稳态所必需的。ncrna受转录、转录后、翻译和翻译后过程的调控。基因表达的转录后调控是由microrna （miRNA）进行的，这是一类小的ncRNA分子，它们可以通过miRNA种子序列和目标转录物上存在的一个简短的核苷酸序列来识别它们的靶位，该序列被称为miRNA应答元件（MRE）。mirna与靶标之间的这种结合可以通过抑制靶信使RNA （mRNA）的翻译或降解来调节基因的表达。共享MREs的转录本可能参与对中心miRNA池的竞争，这可能对彼此的调节产生间接影响。这种竞争网络被称为竞争内源性rna网络（ceRNET）。许多ncrna，包括环状RNA、假基因和长链非编码RNA，以及编码RNA转录物mRNA，组成了ceRNET。这些成分在转录后调控中起着至关重要的作用，并参与许多病理疾病的诊断和治疗。本文综述了ceRNET的作用机制及其主要成分，以及它们在癌症、糖尿病、神经系统、心血管、肝脏和呼吸系统疾病等不同疾病中的治疗意义。

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引用次数: 0

Bioinformatic meta-analysis of transcriptomics of developing Drosophila muscles identifies temporal regulatory transcription factors including a Notch effector 对果蝇肌肉发育过程中的转录组学进行生物信息学元分析，发现了包括缺口效应器在内的时间调控转录因子。

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2024-11-08 DOI: 10.1016/j.bbagrm.2024.195066

Amartya Mukherjee , Fathima Ashraf , Upendra Nongthomba

The intricate mechanism of gene regulation coordinates the precise control of when, where, and to what extent genes are activated or repressed, directing the complex processes that govern cellular functions and development. Dysregulation of gene expression can lead to diseases such as autoimmune disorders, cancer, and neurodegeneration. Transcriptional regulation, especially involving transcription factors (TFs), plays a major role in controlling gene expression. This study focuses on identifying gene regulatory mechanisms that generate distinct gene expression patterns during Drosophila muscle development. Utilising a bioinformatics approach, we analysed the developmental time-point-specific transcriptomics resource generated by Spletter et al., which includes mRNA sequencing data at eight stages of indirect flight muscle (IFM) development. They had identified 40 distinct genome-wide clusters representing various temporal expression dynamics using 'soft' clustering. Promoter sequences of genes in these clusters were analysed to predict novel motifs that act as TF binding sites. Comparative analysis with known motifs revealed significant overlaps, indicating shared transcriptional regulation. The physiological relevance of predicted TFs was confirmed by cross-referencing with experimental ChIP-seq data. We focused on Cluster 36, characterised by a unique bimodal temporal expression profile, and identified candidate genes, Rbfox1 and zfh1, for further study. Ectopic overexpression experiments revealed that the TF Enhancer of split m8 helix-loop-helix [E(spl)m8-HLH], part of the Notch signalling pathway, acts as a transcriptional repressor for Rbfox1 and zfh1. Our findings highlight the complexity of transcriptional regulation during myogenesis, and identify key TFs that could be targeted for further research in muscle development and related disorders.

基因调控的机制错综复杂，它对基因何时、何地以及在何种程度上被激活或抑制进行精确控制，从而引导着支配细胞功能和发育的复杂过程。基因表达失调可导致自身免疫性疾病、癌症和神经变性等疾病。转录调控，尤其是涉及转录因子（TFs）的转录调控，在控制基因表达方面发挥着重要作用。本研究的重点是确定果蝇肌肉发育过程中产生不同基因表达模式的基因调控机制。利用生物信息学方法，我们分析了 Spletter 等人生成的发育时点特异性转录组学资源，其中包括间接飞行肌（IFM）发育八个阶段的 mRNA 测序数据。他们利用 "软 "聚类方法确定了 40 个不同的全基因组集群，代表了不同的时间表达动态。他们分析了这些簇中基因的启动子序列，以预测可作为 TF 结合位点的新图案。与已知基团的比较分析显示出明显的重叠，表明存在共同的转录调控。通过与实验性 ChIP-seq 数据进行交叉比对，确认了预测的 TFs 的生理相关性。我们重点研究了以独特的双峰时间表达谱为特征的簇36，并确定了候选基因Rbfox1和zfh1以作进一步研究。异位过表达实验显示，作为Notch信号通路一部分的TF Enhancer of split m8 helix- loop-helix[E(spl)m8-HLH]是Rbfox1和zfh1的转录抑制因子。我们的发现突显了肌肉发生过程中转录调控的复杂性，并确定了可作为肌肉发育及相关疾病进一步研究目标的关键 TFs。

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