Pub Date : 2025-04-04DOI: 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.
{"title":"Hypoxia inducible factor HIF1α elevates expression of mRNA capping enzyme during cobalt chloride-induced hypoxia.","authors":"Safirul Islam, Chandrama Mukherjee","doi":"10.1016/j.bbagrm.2025.195087","DOIUrl":"https://doi.org/10.1016/j.bbagrm.2025.195087","url":null,"abstract":"<p><p>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 CoCl<sub>2</sub> induced hypoxia on cCE and its function in regulating the substrate lncRNAs. Here, we show that CoCl<sub>2</sub> 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 CoCl<sub>2</sub> induced hypoxia. These results suggest that cCE, upregulated by HIF1α, may act as a posttranscriptional modulator for a few cCE-targeted lncRNAs.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195087"},"PeriodicalIF":2.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 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.
{"title":"Transcription factors associated with regulation of transcriptome in human thigh and calf muscles at baseline and after six days of disuse","authors":"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","doi":"10.1016/j.bbagrm.2025.195086","DOIUrl":"10.1016/j.bbagrm.2025.195086","url":null,"abstract":"<div><div>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 <em>m. soleus</em> – a “slow” muscle with a strong postural function, and “mixed” <em>m. vastus lateralis</em>. 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 <em>m. soleus</em> 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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 2","pages":"Article 195086"},"PeriodicalIF":2.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.bbagrm.2025.195078
Sukesh R. Bhaumik
{"title":"UPS regulation of gene expression and genome integrity","authors":"Sukesh R. Bhaumik","doi":"10.1016/j.bbagrm.2025.195078","DOIUrl":"10.1016/j.bbagrm.2025.195078","url":null,"abstract":"","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195078"},"PeriodicalIF":2.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 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.
{"title":"TAP-MS analysis of FACT interactions and regulation by a ubiquitin ligase, San1","authors":"Priyanka Barman, Pritam Chakraborty, Shalini Guha, Amala Kaja, Rhea Bhaumik, Sukesh R. Bhaumik","doi":"10.1016/j.bbagrm.2025.195077","DOIUrl":"10.1016/j.bbagrm.2025.195077","url":null,"abstract":"<div><div>An evolutionarily conserved heterodimeric FACT (<u>Fa</u>cilitates <u>c</u>hromatin <u>t</u>ranscription) 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 (<u>U</u>biquitin-<u>p</u>roteasome <u>s</u>ystem) regulation, which could reveal new FACT interactors with mechanistic and functional implications. Here, we have adopted a proteome-wide approach via TAP (<u>T</u>andem <u>a</u>ffinity <u>p</u>urification)-mediated pull-down of FACT and its interactors from the soluble and insoluble cellular fractions followed by MS (<u>M</u>ass-<u>s</u>pectrometry) 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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195077"},"PeriodicalIF":2.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 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.
{"title":"Susceptibility to pseudoexfoliation linked to intronic variant rs4926246 in CACNA1A: Evidence from an Indian population study","authors":"Bushra Hayat , Swagatika Panigrahi , Senjit Ram Behera , Pranjya Paramita Mohanty , Debasmita Pankaj Alone","doi":"10.1016/j.bbagrm.2025.195076","DOIUrl":"10.1016/j.bbagrm.2025.195076","url":null,"abstract":"<div><div>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 <em>CACNA1A</em> (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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195076"},"PeriodicalIF":2.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 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.
{"title":"Transcriptional responses of three slc39a/zip members (zip4, zip5 and zip9) and their roles in Zn metabolism in grass carp (Ctenopharyngodon idella)","authors":"Jia-Cheng Guo , Peng-Cheng Xu , Yi-Chuang Xu , Tian-Hua Zhang , Lu-Lu Liu , Tao Liu , Zhi Luo","doi":"10.1016/j.bbagrm.2024.195075","DOIUrl":"10.1016/j.bbagrm.2024.195075","url":null,"abstract":"<div><div>In order to explore the regulatory mechanism of <em>zip4</em>, <em>zip5</em> and <em>zip9</em> in zinc metabolism of grass carp (<em>Ctenopharyngodon idella</em>), the effects of zinc (Zn) on the mRNA expression of <em>zip4</em>, <em>zip5</em> and <em>zip9</em> were investigated. Compared to the control, the mRNA levels of <em>zip4</em> and <em>zip9</em> were significantly reduced under low and high zinc in L8824 cells; the mRNA expression level of <em>zip5</em> 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 <em>zip4</em>, <em>zip5</em> and <em>zip9</em> 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 <em>zip5</em> promoter and at −1679/−1689 bp of <em>zip9</em> promoter. Similarly, krüppel-like factor 4 (KLF4) could specifically bind to the −599/−609 bp sequence on the <em>zip5</em> promoter and the −261/−272 bp sequence on the <em>zip9</em> promoter. The results of electrophoretic mobility-shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) indicated that Zn incubation increased DNA binding capacity of STAT3 to <em>zip5</em> and <em>zip9</em> promoters, and decreased DNA binding capacity of KLF4 to <em>zip5</em> and <em>zip9</em> promoters. This study provides a good basis for elucidating the regulatory mechanism of zinc metabolism in the vertebrates.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195075"},"PeriodicalIF":2.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 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.
{"title":"Experimental approaches to investigate biophysical interactions between homeodomain transcription factors and DNA","authors":"Fadwa Mekkaoui , Robert A. Drewell , Jacqueline M. Dresch , Donald E. Spratt","doi":"10.1016/j.bbagrm.2024.195074","DOIUrl":"10.1016/j.bbagrm.2024.195074","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195074"},"PeriodicalIF":2.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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: 10.1016/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.
{"title":"Competing endogenous RNAs network and therapeutic implications: New horizons in disease research","authors":"Nahla E. El-Ashmawy , Eman G. Khedr , Renad T. Darwish , Amera O. Ibrahim","doi":"10.1016/j.bbagrm.2024.195073","DOIUrl":"10.1016/j.bbagrm.2024.195073","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195073"},"PeriodicalIF":2.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Bioinformatic meta-analysis of transcriptomics of developing Drosophila muscles identifies temporal regulatory transcription factors including a Notch effector","authors":"Amartya Mukherjee , Fathima Ashraf , Upendra Nongthomba","doi":"10.1016/j.bbagrm.2024.195066","DOIUrl":"10.1016/j.bbagrm.2024.195066","url":null,"abstract":"<div><div>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 <em>Drosophila</em> muscle development. Utilising a bioinformatics approach, we analysed the developmental time-point-specific transcriptomics resource generated by Spletter <em>et al</em>., 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, <em>Rbfox1</em> and <em>zfh1</em>, 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 <em>Rbfox1</em> and <em>zfh1</em>. 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.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 1","pages":"Article 195066"},"PeriodicalIF":2.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.bbagrm.2024.195065
Haitham Sobhy , Marco De Rovere , Amina Ait-Ammar , Muhammad Kashif , Clementine Wallet , Fadoua Daouad , Thomas Loustau , Carine Van Lint , Christian Schwartz , Olivier Rohr
BCL11b is a transcription regulator and a tumor suppressor involved in lymphomagenesis, central nervous system (CNS) and immune system developments. BCL11b favors persistence of HIV latency and contributes to control cell cycle, differentiation and apoptosis in multiple organisms and cell models. Although BCL11b recruits the non-coding RNA 7SK and epigenetic enzymes to regulate gene expression, BCL11b-associated ribonucleoprotein complexes are unknown. Thanks to CLIP-seq and quantitative LC-MS/MS mass spectrometry approaches complemented with systems biology validations, we show that BCL11b interacts with RNA splicing and non-sense-mediated decay proteins, including FUS, SMN1, UPF1 and Drosha, which may contribute in isoform selection of protein-coding RNA isoforms from noncoding-RNAs isoforms (retained introns or nonsense mediated RNA). Interestingly, BCL11b binds to RNA transcripts and proteins encoded by the same genes (FUS, ESWR1, CHD and Tubulin). Our study highlights that BCL11b targets RNA processing and splicing proteins, and RNAs that implicate cell cycle, development, neurodegenerative, and cancer pathways. These findings will help future mechanistic understanding of developmental disorders.
Importance
BCL11b-protein and RNA interactomes reveal BLC11b association with specific nucleoprotein complexes involved in the regulation of genes expression.
BCL11b interacts with RNA processing and splicing proteins.
{"title":"BCL11b interacts with RNA and proteins involved in RNA processing and developmental diseases","authors":"Haitham Sobhy , Marco De Rovere , Amina Ait-Ammar , Muhammad Kashif , Clementine Wallet , Fadoua Daouad , Thomas Loustau , Carine Van Lint , Christian Schwartz , Olivier Rohr","doi":"10.1016/j.bbagrm.2024.195065","DOIUrl":"10.1016/j.bbagrm.2024.195065","url":null,"abstract":"<div><div>BCL11b is a transcription regulator and a tumor suppressor involved in lymphomagenesis, central nervous system (CNS) and immune system developments. BCL11b favors persistence of HIV latency and contributes to control cell cycle, differentiation and apoptosis in multiple organisms and cell models. Although BCL11b recruits the non-coding RNA 7SK and epigenetic enzymes to regulate gene expression, BCL11b-associated ribonucleoprotein complexes are unknown. Thanks to CLIP-seq and quantitative LC-MS/MS mass spectrometry approaches complemented with systems biology validations, we show that BCL11b interacts with RNA splicing and non-sense-mediated decay proteins, including FUS, SMN1, UPF1 and Drosha, which may contribute in isoform selection of protein-coding RNA isoforms from noncoding-RNAs isoforms (retained introns or nonsense mediated RNA). Interestingly, BCL11b binds to RNA transcripts and proteins encoded by the same genes (FUS, ESWR1, CHD and Tubulin). Our study highlights that BCL11b targets RNA processing and splicing proteins, and RNAs that implicate cell cycle, development, neurodegenerative, and cancer pathways. These findings will help future mechanistic understanding of developmental disorders.</div></div><div><h3>Importance</h3><div>BCL11b-protein and RNA interactomes reveal BLC11b association with specific nucleoprotein complexes involved in the regulation of genes expression.</div><div>BCL11b interacts with RNA processing and splicing proteins.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1867 4","pages":"Article 195065"},"PeriodicalIF":2.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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