MRG15 orchestrates rhythmic epigenomic remodelling and controls hepatic lipid metabolism.

Nature Metabolism
Yuda WeiQiurong Ding

Abstract

The rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. The Rev-erbα-HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes; however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15, which is encoded by the mortality factor on chromosome 4 (MORF4)-related gene on chromosome 15, displays a significant diurnal rhythm and activates lipid genes in the mouse liver. RNA polymerase II (Pol II) recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. MRG15 interacts with the nuclear receptor LRH-1, rather than with known core clock proteins, and is recruited to genomic loci near lipid genes via LRH-1. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in the rhythmic regulation of hepatic lipid metabolism.

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Citations

Apr 17, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Yu SunKristina Schoonjans

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Datasets Mentioned

BETA
GSE89877

Methods Mentioned

BETA
histone acetylation
acetylation
immunoprecipitation
RNA-seq
co-immunoprecipitation
nuclear magnetic resonance
ChIP
PCR
ELISA
Transfection

Software Mentioned

Imaris
LiftOver
findMotifsGenome
Image Studio
R scripts
Python
ChIPseeker
GraphPad Prism
STAR
DEseq

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