Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice

Zhengyi Zhang, An-Chieh Feng, David Salisbury, Xin Liu, Xiaohui Wu, Jason Kim, Irina Lapina, Dan Wang, Brennan Lee, Josue Fraga, Calvin Pan, Kevin J. Williams, Aldons J. Lusis, Phil Scumpia and Tamer Sallam ()
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Zhengyi Zhang: University of California
An-Chieh Feng: University of California
David Salisbury: University of California
Xin Liu: University of California
Xiaohui Wu: University of California
Jason Kim: University of California
Irina Lapina: University of California
Dan Wang: University of California
Brennan Lee: University of California
Josue Fraga: University of California
Calvin Pan: University of California
Kevin J. Williams: University of California
Aldons J. Lusis: University of California
Phil Scumpia: University of California
Tamer Sallam: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states.

Date: 2020
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DOI: 10.1038/s41467-020-14711-4

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