Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function

Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that p
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
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Metadaten
Author:Jun-ichi Sakamak, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O’Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S. Long, Maria New, Tim van Acker, Sharon A. Tooze, Scott W. Lowe, Ivan Dikic, Kevin M. Ryan
URN:urn:nbn:de:hebis:30:3-439119
DOI:http://dx.doi.org/10.1016/j.molcel.2017.04.027
ISSN:1097-4164
ISSN:1097-2765
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28525743
Parent Title (German):Molecular cell
Publisher:Cell Press ; Elsevier
Place of publication:[Cambridge, Mass.] ; New York, NY
Document Type:Article
Language:English
Date of Publication (online):2017/10/26
Date of first Publication:2017/05/18
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/10/26
Tag:AMPK; BRD4; BRD4-NUT; G9a/EHMT2/KMT1C; SIRT1; autophagy; hMOF/KAT8; lysosomes; selective autophagy; transcriptional regulation of autophagy
Volume:66
Issue:4, e9
Pagenumber:26
First Page:517
Last Page:532
Note:
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
HeBIS PPN:451284070
Institutes:Medizin
Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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