The long noncoding RNA CHROME regulates cholesterol homeostasis in primates

Nature Metabolism
Elizabeth J HennessyKathryn J Moore

Abstract

The human genome encodes thousands of long noncoding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), which is elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, and regulates cellular and systemic cholesterol homeostasis. Expression of the lncRNA CHROME is influenced by dietary and cellular cholesterol through the sterol-activated liver X receptor transcription factors, which control genes that mediate responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and high-density lipoprotein (HDL) biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases the levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing the expression of their overlapping target gene networks and associated biological functions. In particular, cells that lack CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central compon...Continue Reading

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Datasets Mentioned

BETA
E-MTAB-5477
GSE97469

Methods Mentioned

BETA
PCR
immunoprecipitation
RNA-seq
antisense oligonucleotides
lipidation
affinity purification
biopsies
transfection
PMA
Protein Assay

Clinical Trials Mentioned

NCT02106429
NCT01897103

Software Mentioned

CHROME
PRISM
R
STAR Aligner
PhastCons
Image Studio
BiKE
miRhub
SAS
GraphPad

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