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

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

doi:10.1038/s41467-020-14711-4

Zhengyi Zhang, Tamer Sallam + Show 13 more

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https://doi.org/10.1038/s41467-020-14711-4

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Journal: Nature Communications	Publication Date: Feb 20, 2020
Citations: 11	License type: open-access

Affiliation: University of California, Los Angeles

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.

Highlights

Heterogeneous nuclear ribonucleoproteins are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA
Since RALY is one of the few Heterogeneous nuclear ribonucleoproteins (hnRNPs) linked to human lipid traits, and since our previous studies have shown that disruption of the LeXis-RALY axis perturbs cholesterogenic gene expression, we sought to determine the effect of genetic deletion of Raly on Srebp[2] gene expression
Deletion of Raly from primary murine hepatocytes led to a significant reduction of Srebp[2] and its target genes involved in cholesterol biosynthesis, including Hmgcr (Supplementary Fig. 2c)

Summary

Introduction

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. We find that RALY binds the promoter region of the master metabolic regulator Srebp[2] and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. The sterol regulatory element-binding proteins (SREBPs) are master regulators of sterol metabolism, directly activating the expression of genes involved in cholesterol and fatty acid biosynthesis[9]. Consistent with unique epistatic relationship between various SREBPs, loss of SREBP2 in mouse liver reduces SREBP1c and triglyceride levels in addition to impacting cholesterol stores[11] Despite their unique activation signature both isoforms appear to bind similar DNA response elements and to partner with common transcriptional coactivators, including Nuclear Transcription Factor Y (NFY) and SP1 Our work offers insights into mechanisms orchestrating selective promoter activation and a model by which hnRNPs can impact metabolic disease states

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