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 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. Overall design: RNA-Seq of KP-4 pancreatic adenocarcinoma cells transfected with control, BRD4 #1 or BRD4 #2 siRNA for 72hrs (n=3 independent sample preparations)

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Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O'Prey J, Clark W, Hedley A, Nixon C, Long JS, New M, Van Acker T, Tooze SA, Lowe SW, Dikic I, Ryan KM