Meghan M Conner, Haley V Parker, Daniela R Falcone, Gehoon Chung, Christine E Schaner Tooley
{"title":"Novel regulation of the transcription factor ZHX2 by N-terminal methylation.","authors":"Meghan M Conner, Haley V Parker, Daniela R Falcone, Gehoon Chung, Christine E Schaner Tooley","doi":"10.1080/21541264.2022.2079184","DOIUrl":"https://doi.org/10.1080/21541264.2022.2079184","url":null,"abstract":"<p><p>N-terminal methylation (Nα-methylation) by the methyltransferase NRMT1 is an important post-translational modification that regulates protein-DNA interactions. Accordingly, its loss impairs functions that are reliant on such interactions, including DNA repair and transcriptional regulation. The global loss of Nα-methylation results in severe developmental and premature aging phenotypes, but given over 300 predicted substrates, it is hard to discern which physiological substrates contribute to each phenotype. One of the most striking phenotypes in NRMT1 knockout (<i>Nrmt1<sup>-/-</sup></i>) mice is early liver degeneration. To identify the disrupted signaling pathways leading to this phenotype and the NRMT1 substrates involved, we performed RNA-sequencing analysis of control and <i>Nrmt1<sup>-/-</sup></i> adult mouse livers. We found both a significant upregulation of transcripts in the cytochrome P450 (CYP) family and downregulation of transcripts in the major urinary protein (MUP) family. Interestingly, transcription of both families is inversely regulated by the transcription factor zinc fingers and homeoboxes 2 (ZHX2). ZHX2 contains a non-canonical NRMT1 consensus sequence, indicating that its function could be directly regulated by Nα-methylation. We confirmed misregulation of CYP and MUP mRNA and protein levels in <i>Nrmt1<sup>-/-</sup></i> livers and verified NRMT1 can methylate ZHX2 <i>in vitro</i>. In addition, we used a mutant of ZHX2 that cannot be methylated to directly demonstrate Nα-methylation promotes ZHX2 transcription factor activity and target promoter occupancy. Finally, we show <i>Nrmt1<sup>-/-</sup></i> mice also exhibit early postnatal de-repression of ZHX2 targets involved in fetal liver development. Taken together, these data implicate ZHX2 misregulation as a driving force behind the liver phenotype seen in <i>Nrmt1<sup>-/-</sup></i> mice.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"13 1-3","pages":"1-15"},"PeriodicalIF":3.6,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467584/pdf/KTRN_13_2079184.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9518748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2022-02-01Epub Date: 2022-09-01DOI: 10.1080/21541264.2022.2108302
Elisabeth Altendorfer, Yelizaveta Mochalova, Andreas Mayer
{"title":"BRD4: a general regulator of transcription elongation.","authors":"Elisabeth Altendorfer, Yelizaveta Mochalova, Andreas Mayer","doi":"10.1080/21541264.2022.2108302","DOIUrl":"https://doi.org/10.1080/21541264.2022.2108302","url":null,"abstract":"<p><p>Transcription elongation by RNA polymerase II (Pol II) has emerged as a regulatory hub in gene expression. A key control point occurs during early transcription elongation when Pol II pauses in the promoter-proximal region at the majority of genes in mammalian cells and at a large set of genes in <i>Drosophila</i>. An increasing number of <i>trans</i>-acting factors have been linked to promoter-proximal pausing. Some factors help to establish the pause, whereas others are required for the release of Pol II into productive elongation. A dysfunction of this elongation control point leads to aberrant gene expression and can contribute to disease development. The BET bromodomain protein BRD4 has been implicated in elongation control. However, only recently direct BRD4-specific functions in Pol II transcription elongation have been uncovered. This mainly became possible with technological advances that allow selective and rapid ablation of BRD4 in cells along with the availability of approaches that capture the immediate consequences on nascent transcription. This review sheds light on the experimental breakthroughs that led to the emerging view of BRD4 as a general regulator of transcription elongation.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":" ","pages":"70-81"},"PeriodicalIF":3.6,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40337396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2022-02-01Epub Date: 2022-07-25DOI: 10.1080/21541264.2022.2103366
Aixia Song, Fei Xavier Chen
{"title":"The pleiotropic roles of SPT5 in transcription.","authors":"Aixia Song, Fei Xavier Chen","doi":"10.1080/21541264.2022.2103366","DOIUrl":"https://doi.org/10.1080/21541264.2022.2103366","url":null,"abstract":"<p><p>Initially discovered by genetic screens in budding yeast, SPT5 and its partner SPT4 form a stable complex known as DSIF in metazoa, which plays pleiotropic roles in multiple steps of transcription. SPT5 is the most conserved transcription elongation factor, being found in all three domains of life; however, its structure has evolved to include new domains and associated posttranslational modifications. These gained features have expanded transcriptional functions of SPT5, likely to meet the demand for increasingly complex regulation of transcription in higher organisms. This review discusses the pleiotropic roles of SPT5 in transcription, including RNA polymerase II (Pol II) stabilization, enhancer activation, Pol II pausing and its release, elongation, and termination, with a focus on the most recent progress of SPT5 functions in regulating metazoan transcription.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":" ","pages":"53-69"},"PeriodicalIF":3.6,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/12/b8/KTRN_13_2103366.PMC9467590.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40623448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-10-01Epub Date: 2021-12-07DOI: 10.1080/21541264.2021.2009421
Takashi Yamazaki, Lizhi Liu, James L Manley
{"title":"Oxidative stress induces Ser 2 dephosphorylation of the RNA polymerase II CTD and premature transcription termination.","authors":"Takashi Yamazaki, Lizhi Liu, James L Manley","doi":"10.1080/21541264.2021.2009421","DOIUrl":"https://doi.org/10.1080/21541264.2021.2009421","url":null,"abstract":"<p><p>The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) consists of YSPTSPS heptapeptide repeats, and the phosphorylation status of the repeats controls multiple transcriptional steps and co-transcriptional events. However, how CTD phosphorylation status responds to distinct environmental stresses is not fully understood. In this study, we found that a drastic reduction in phosphorylation of a subset of Ser2 residues occurs rapidly but transiently following exposure to H<sub>2</sub>O<sub>2</sub>. ChIP analysis indicated that Ser2-P, and to a lesser extent Tyr1-P was reduced only at the gene 3' end. Significantly, the levels of polyadenylation factor CstF77, as well as Pol II, were also reduced. However, no increase in uncleaved or readthrough RNA products was observed, suggesting transcribing Pol II prematurely terminates at the gene end in response to H<sub>2</sub>O<sub>2</sub>. Further analysis found that the reduction of Ser2-P is, at least in part, regulated by CK2 but independent of FCP1 and other known Ser2 phosphatases. Finally, the H<sub>2</sub>O<sub>2</sub> treatment also affected snRNA 3' processing although surprisingly the U2 processing was not impaired. Together, our data suggest that H<sub>2</sub>O<sub>2</sub> exposure creates a unique CTD phosphorylation state that rapidly alters transcription to deal with acute oxidative stress, perhaps creating a novel \"emergency brake\" mechanism to transiently dampen gene expression.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":" ","pages":"277-293"},"PeriodicalIF":3.6,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208776/pdf/KTRN_12_2009421.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39952978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"m<sup>6</sup>A RNA modification in transcription regulation.","authors":"Junaid Akhtar, Margot Lugoboni, Guillaume Junion","doi":"10.1080/21541264.2022.2057177","DOIUrl":"https://doi.org/10.1080/21541264.2022.2057177","url":null,"abstract":"<p><p>RNA modifications are prevalent among all the classes of RNA, regulate diverse biological processes, and have emerged as a key regulatory mechanism in post-transcriptional control of gene expression. They are subjected to precise spatial and temporal control and shown to be critical for the maintenance of normal development and physiology. For example, m<sup>6</sup>A modification of mRNA affects stability, recruitment of RNA binding protein (RBP), translation, and splicing. The deposition of m6A on the RNA happens co-transcriptionally, allowing the tight coupling between the transcription and RNA modification machinery. The m<sup>6</sup>A modification is affected by transcriptional dynamics, but recent insights also suggest that m<sup>6</sup>A machinery impacts transcription and chromatin signature.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 5","pages":"266-276"},"PeriodicalIF":3.6,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208771/pdf/KTRN_12_2057177.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9248284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-10-01Epub Date: 2022-03-20DOI: 10.1080/21541264.2022.2047583
Moritz M Pfleiderer, Wojciech P Galej
{"title":"Emerging insights into the function and structure of the Integrator complex.","authors":"Moritz M Pfleiderer, Wojciech P Galej","doi":"10.1080/21541264.2022.2047583","DOIUrl":"10.1080/21541264.2022.2047583","url":null,"abstract":"<p><p>The Integrator was originally discovered as a specialized 3'-end processing endonuclease complex required for maturation of RNA polymerase II (RNAPII)-dependent small nuclear RNAs (snRNAs). Since its discovery, Integrator's spectrum of substrates was significantly expanded to include non-polyadenylated long noncoding RNAs (lncRNA), enhancer RNAs (eRNAs), telomerase RNA (tertRNA), several Herpesvirus transcripts, and messenger RNAs (mRNAs). Recently emerging transcriptome-wide studies reveled an important role of the Integrator in protein-coding genes, where it contributes to gene expression regulation through promoter-proximal transcription attenuation. These new functional data are complemented by several structures of Integrator modules and higher-order complexes, providing mechanistic insights into Integrator-mediated processing events. In this work, we summarize recent progress in our understanding of the structure and function of the Integrator complex.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 5","pages":"251-265"},"PeriodicalIF":3.6,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10496717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-08-01Epub Date: 2021-09-27DOI: 10.1080/21541264.2021.1981713
Michael W Webster, Albert Weixlbaumer
{"title":"Macromolecular assemblies supporting transcription-translation coupling.","authors":"Michael W Webster, Albert Weixlbaumer","doi":"10.1080/21541264.2021.1981713","DOIUrl":"https://doi.org/10.1080/21541264.2021.1981713","url":null,"abstract":"<p><p>Coordination between the molecular machineries that synthesize and decode prokaryotic mRNAs is an important layer of gene expression control known as transcription-translation coupling. While it has long been known that translation can regulate transcription and vice-versa, recent structural and biochemical work has shed light on the underlying mechanistic basis. Complexes of RNA polymerase linked to a trailing ribosome (expressomes) have been structurally characterized in a variety of states at near-atomic resolution, and also directly visualized in cells. These data are complemented by recent biochemical and biophysical analyses of transcription-translation systems and the individual components within them. Here, we review our improved understanding of the molecular basis of transcription-translation coupling. These insights are discussed in relation to our evolving understanding of the role of coupling in cells.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 4","pages":"103-125"},"PeriodicalIF":3.6,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632081/pdf/KTRN_12_1981713.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39454737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-08-01Epub Date: 2021-08-17DOI: 10.1080/21541264.2021.1964328
Michael Miller, Aaron J Oakley, Peter J Lewis
{"title":"RNA polymerases from low G+C gram-positive bacteria.","authors":"Michael Miller, Aaron J Oakley, Peter J Lewis","doi":"10.1080/21541264.2021.1964328","DOIUrl":"https://doi.org/10.1080/21541264.2021.1964328","url":null,"abstract":"<p><p>The low G + C Gram-positive bacteria represent some of the most medically and industrially important microorganisms. They are relied on for the production of food and dietary supplements, enzymes and antibiotics, as well as being responsible for the majority of nosocomial infections and serving as a reservoir for antibiotic resistance. Control of gene expression in this group is more highly studied than in any bacteria other than the Gram-negative model Escherichia coli, yet until recently no structural information on RNA polymerase (RNAP) from this group was available. This review will summarize recent reports on the high-resolution structure of RNAP from the model low G + C representative Bacillus subtilis, including the role of auxiliary subunits <b>δ</b> and <b>ε</b>, and outline approaches for the development of antimicrobials to target RNAP from this group.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 4","pages":"92-102"},"PeriodicalIF":3.6,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632073/pdf/KTRN_12_1964328.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39319374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-08-01Epub Date: 2021-11-01DOI: 10.1080/21541264.2021.1997315
Jin Qian, Wenxuan Xu, David Dunlap, Laura Finzi
{"title":"Single-molecule insights into torsion and roadblocks in bacterial transcript elongation.","authors":"Jin Qian, Wenxuan Xu, David Dunlap, Laura Finzi","doi":"10.1080/21541264.2021.1997315","DOIUrl":"10.1080/21541264.2021.1997315","url":null,"abstract":"<p><p>During transcription, RNA polymerase (RNAP) translocates along the helical template DNA while maintaining high transcriptional fidelity. However, all genomes are dynamically twisted, writhed, and decorated by bound proteins and motor enzymes. In prokaryotes, proteins bound to DNA, specifically or not, frequently compact DNA into conformations that may silence genes by obstructing RNAP. Collision of RNAPs with these architectural proteins, may result in RNAP stalling and/or displacement of the protein roadblock. It is important to understand how rapidly transcribing RNAPs operate under different levels of supercoiling or in the presence of roadblocks. Given the broad range of asynchronous dynamics exhibited by transcriptional complexes, single-molecule assays, such as atomic force microscopy, fluorescence detection, optical and magnetic tweezers, etc. are well suited for detecting and quantifying activity with adequate spatial and temporal resolution. Here, we summarize current understanding of the effects of torsion and roadblocks on prokaryotic transcription, with a focus on single-molecule assays that provide real-time detection and readout.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 4","pages":"219-231"},"PeriodicalIF":3.6,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632135/pdf/KTRN_12_1997315.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39830211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transcription-AustinPub Date : 2021-08-01Epub Date: 2021-09-09DOI: 10.1080/21541264.2021.1973865
Haley M Amemiya, Jeremy Schroeder, Peter L Freddolino
{"title":"Nucleoid-associated proteins shape chromatin structure and transcriptional regulation across the bacterial kingdom.","authors":"Haley M Amemiya, Jeremy Schroeder, Peter L Freddolino","doi":"10.1080/21541264.2021.1973865","DOIUrl":"10.1080/21541264.2021.1973865","url":null,"abstract":"<p><p>Genome architecture has proven to be critical in determining gene regulation across almost all domains of life. While many of the key components and mechanisms of eukaryotic genome organization have been described, the interplay between bacterial DNA organization and gene regulation is only now being fully appreciated. An increasing pool of evidence has demonstrated that the bacterial chromosome can reasonably be thought of as chromatin, and that bacterial chromosomes contain transcriptionally silent and transcriptionally active regions analogous to heterochromatin and euchromatin, respectively. The roles played by histones in eukaryotic systems appear to be shared across a range of nucleoid-associated proteins (NAPs) in bacteria, which function to compact, structure, and regulate large portions of bacterial chromosomes. The broad range of extant NAPs, and the extent to which they differ from species to species, has raised additional challenges in identifying and characterizing their roles in all but a handful of model bacteria. Here we review the regulatory roles played by NAPs in several well-studied bacteria and use the resulting state of knowledge to provide a working definition for NAPs, based on their function, binding pattern, and expression levels. We present a screening procedure which can be applied to any species for which transcriptomic data are available. Finally, we note that NAPs tend to play two major regulatory roles - xenogeneic silencers and developmental regulators - and that many unrecognized potential NAPs exist in each bacterial species examined.</p>","PeriodicalId":47009,"journal":{"name":"Transcription-Austin","volume":"12 4","pages":"182-218"},"PeriodicalIF":3.6,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632127/pdf/KTRN_12_1973865.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39398135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}