Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function

Molecular Cell
Jun-Ichi SakamakiK M Ryan

Abstract

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.

Citations

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Datasets Mentioned

BETA
GSE90444

Methods Mentioned

BETA
lipidation
PCR
RNA-seq
immunoprecipitation
ChIP
acetylation
co-immunoprecipitation
histone acetylation
Profiler
Assay

Software Mentioned

FlowJo
CellProfiler
Bioconductor
GraphPad
BD CellQuest Pro
ZEN
DESeq2
R
: Profiler
Bowtie

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