COVID-19, caused by SARS-CoV-2 infection, is associated with atherosclerotic cardiovascular complications like acute coronary syndrome, myocardial infarction, and stroke, but the underlying mechanisms are poorly understood. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression in the immune response. RNA-seq of whole blood from hospitalized patients with COVID-19, influenza A virus and matched controls identified 190 lncRNAs deregulated in both viral infections. Among the top mutually upregulated lncRNAs, we noted
CHROMR
(alias
CHROME
)
,
a primate-specific lncRNA previously identified as a competing endogenous RNA that regulates cholesterol efflux and fatty acid oxidation via microRNA sequestration. Here, we report a complementary role for
CHROMR
in coordinating the interferon (IFN) signaling response to respiratory viruses.
CHROMR
expression is induced in macrophages in response to SARS-CoV-2 and influenza A infection and accumulates in the nucleus where it binds the transcriptional co-repressor IRF2BP2, a negative regulator of IFN-stimulated gene (ISG) expression.
CHROMR
is essential for mounting an anti-viral response, as its depletion in macrophages reduces histone acetylation at ISGs, activation of IRF signaling, and ISG expression. These findings suggest that
CHROMR
sequesters the nuclear IRF-2/IRF2BP2 repressor complex releasing its inhibitory effect on transcription of ISGs. Consistent with this,
CHROMR
expression is required to restrict influenza virus replication in macrophages. Notably, many viruses rewire host lipid synthesis and metabolism to facilitate replication, and thus, increased
CHROMR
expression in virus infected cells would both mitigate cellular lipid accumulation and increase ISG transcription to mount an anti-viral immune response. Collectively, our findings underscore the merit of investigating lncRNAs to decipher novel regulatory mechanisms that govern lipid metabolism and inflammation in humans.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.