TY - JOUR
T1 - The long noncoding RNA CHROME regulates cholesterol homeostasis in primates
AU - Hennessy, Elizabeth J.
AU - van Solingen, Coen
AU - Scacalossi, Kaitlyn R.
AU - Ouimet, Mireille
AU - Afonso, Milessa S.
AU - Prins, Jurrien
AU - Koelwyn, Graeme J.
AU - Sharma, Monika
AU - Ramkhelawon, Bhama
AU - Carpenter, Susan
AU - Busch, Albert
AU - Chernogubova, Ekaterina
AU - Matic, Ljubica Perisic
AU - Hedin, Ulf
AU - Maegdefessel, Lars
AU - Caffrey, Brian E.
AU - Hussein, Maryem A.
AU - Ricci, Emiliano P.
AU - Temel, Ryan E.
AU - Garabedian, Michael J.
AU - Berger, Jeffrey S.
AU - Vickers, Kasey C.
AU - Kanke, Matthew
AU - Sethupathy, Praveen
AU - Teupser, Daniel
AU - Holdt, Lesca M.
AU - Moore, Kathryn J.
N1 - Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 component of the noncoding RNA circuitry that controls cholesterol homeostasis in humans.
AB - 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 component of the noncoding RNA circuitry that controls cholesterol homeostasis in humans.
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U2 - 10.1038/s42255-018-0004-9
DO - 10.1038/s42255-018-0004-9
M3 - Article
C2 - 31410392
AN - SCOPUS:85070950057
VL - 1
SP - 98
EP - 110
JO - Nature Metabolism
JF - Nature Metabolism
IS - 1
ER -