BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
02
11
2020
accepted:
06
04
2021
entrez:
27
5
2021
pubmed:
28
5
2021
medline:
16
4
2022
Statut:
epublish
Résumé
The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation-dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.
Identifiants
pubmed: 34039605
pii: 7/22/eabf5374
doi: 10.1126/sciadv.abf5374
pmc: PMC8153730
pii:
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Chromatin
0
Nuclear Proteins
0
Transcription Factors
0
Protein Methyltransferases
EC 2.1.1.-
SETD6 protein, human
EC 2.1.1.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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