Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans

101

Accumulation of unfolded or misfolded proteins causes endoplasmic reticulum (ER) stress, which activates a set of ER membraneassociated transcription factors for protein homeostasis regulation. Previous genome-wide chromatin immunoprecipitation analysis shows a strong correlation between histone H3K4 trimethylation (H3K4me3) and active gene expression. However, how the histone modification complex is specifically and timely recruited to the active promoters remains unknown. Using ER stress responsive gene expression as a model system, we demonstrate that sequencespecific transcription factors interact with COMPASS-like components and affect H3K4me3 formation at specific target sites in Arabidopsis. Gene profiling analysis reveals that membrane-associated basic leucine zipper (bZIP) transcription factors bZIP28 and bZIP60 regulate most of the ER stress responsive genes. Loss-offunctions of bZIP28 and bZIP60 impair the occupancy of H3K4me3 on promoter regions of ER stress responsive genes. Further, in vitro pull-down assays and in vivo bimolecular fluorescence complementation (BiFC) experiments show that bZIP28 and bZIP60 interact with Ash2 and WDR5a, both of which are core COMPASS-like components. Knockdown expression of either Ash2 or WDR5a decreased the expression of several ER stress responsive genes. The COMPASSlike complex is known to interact with histone methyltransferase to facilitate preinitiation complex (PIC) assembly and generate H3K4me3 during transcription elongation. Thus, our data shows that the ER stress stimulus causes the formation of PIC and deposition of H3K4me3 mark at specific promoters through the interaction between transcription factor and COMPASS-like components.COMPASS-like | ER stress | H3K4 trimethylation | transcription factor | unfolded protein response

Section: Resultsmentioning

confidence: 99%

Transcription factor interaction with COMPASS-like complex regulates histone H3K4 trimethylation for specific gene expression in plants

Song

Sun

et al. 2015

101

“…In metazoans, RNAPII recruitment and activation are known to regulate signal-dependent gene transcription (9,42,43); however, the factors involved in recruiting and stabilizing RNAPII at the promoter in a contextand gene-specific manner in response to diverse stimuli, including viral infection, are unclear. We demonstrate that Nup98 depletion reduces the level of RNAPII S5P at the promoters of virally induced genes and, consequently, the level of transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…Many primary response genes have active chromatin marks and features of transcriptional pausing, including high occupancy of the initiating form of RNA polymerase II (RNAPII), S5 phosphorylated (S5P) (2,4,6), along with negative elongation factor complex (NELF) and DRB Sensitivity-Inducing Factor complex (DSIF), which prevent transcriptional elongation (4,(6)(7)(8)(9)(10). Paused RNAPII can be activated by the positive transcription elongation factor b (P-TEFb) in a stimulusdependent manner, which phosphorylates NELF, DSIF, and RNAPII to release the pause and promote transcriptional elongation and thus the production of mature mRNAs (9,(11)(12)(13). Indeed, a large number of LPS-induced primary response genes are controlled at the level of pausing including the classical gene TNF-α (4).…”

mentioning

confidence: 99%

Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

Panda

Pascual-Garcia²,

Dunagin

et al. 2014

In response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. While many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. Our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in Drosophila. Moreover, one-half of this program is regulated at the level of transcriptional pausing. Here we found that Nup98, a virus-induced gene, was antiviral against a panel of viruses both in cells and adult flies since its depletion significantly enhanced viral infection. Mechanistically, we found that Nup98 promotes antiviral gene expression in Drosophila at the level of transcription. Expression profiling revealed that the virus-induced activation of 36 genes was abrogated upon loss of Nup98; and we found that a subset of these Nup98-dependent genes were antiviral. These Nup98-dependent virus-induced genes are Cdk9-dependent and translation-independent suggesting that these are rapidly induced primary response genes. Biochemically, we demonstrate that Nup98 is directly bound to the promoters of virus-induced genes, and that it promotes occupancy of the initiating form of RNA polymerase II at these promoters, which are rapidly induced on viral infection to restrict human arboviruses in insects.innate immunity | nuclear pore | nucleoporin | pol II regulation | P-TEFb

“…It has become increasingly clear that the regulation of Pol-II pausing is a major nexus of transcriptional control (14), and the focus of transcription factors as diverse as NF-κB (15), c-Myc (16), and HIF1A (17). Upon Pol-II recruitment to a gene promoter, serine-5 residues within a repeated motif in its carboxyl-terminal domain are phosphorylated by the general transcription factor TFIIH, launching transcription (reviewed in ref.…”

mentioning

confidence: 99%

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Yoshida

Bansal

Schaefer

et al. 2015

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomaincontaining protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.