Unknown,Transcriptomics,Genomics,Proteomics

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Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

ABSTRACT: Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.

ORGANISM(S): Homo sapiens

SUBMITTER: Qi Ma

PROVIDER: E-GEOD-51633 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release.

Liu Wen W Ma Qi Q Wong Kaki K Li Wenbo W Ohgi Kenny K Zhang Jie J Aggarwal Aneel A Rosenfeld Michael G MG

Cell 20131201 7

Distal enhancers characterized by the H3K4me(1) mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here, we report that a unique cohort of jumonji C-domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) cobound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-prox ...[more]

PMID: 24360279

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Project description:The Jumonji domaining-containing protein JMJD6 is a 2-oxoglutarate dependent dioxygenase that has been implicated in a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing and co-transcriptional processing. Although not all studies agree, JMJD6 has been reported to catalyse both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and the indirect implication of JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a site of reported prolyl hydroxylation within a lysine-rich region of the bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalysed by Jmjd6. This prompted a wider search for JMJD6-catalysed protein modifications deploying mass spectrometric methods designed to identify novel substrate associations and facilitate analysis of lysine-rich regions by LC-MSMS. Using derivatization of lysine with propionic anhydride to improve the analysis of tryptic peptides and a pharmacological inhibitor of JMJD6 to stabilise enzyme/substrate associations, we report over 100 sites of JMJD6-catalysed lysyl hydroxylation on 48 protein substrates including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in this study have been associated with membraneless organelle formation. Taken together with findings implicating lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia. Note, this dataset corresponds to Figure 3 of the published manuscript; which employs a substrate-trapping methodology to identify novel substrates of JMJD6 by label free DIA approach.

Dataset Information

Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release

Publications

Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release.

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