GSE133166
Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Although several lines of evidence link hnRNP abnormalities to neurodegenerative diseases and cancer their contribution to metabolic control remains unexplored. Here, we outline a role for hnRNPs in regulatory circuits controlling sterol homoeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways arguing that hnRNPs can discriminately influence regulated gene expression programs. 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 NFY to influence cholesterogenic gene expression. Our work offers new insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact metabolic health and disease states. Overall design: RALY KO and  histone-DNA complexes