Unknown

Dataset Information

0

HIV latency is reversed by ACSS2-driven histone crotonylation.


ABSTRACT: Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.

PROVIDER: S-EPMC5824862 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC2722084 | BioStudies
| S-EPMC6172763 | BioStudies
| S-EPMC5505171 | BioStudies
| S-EPMC4881759 | BioStudies
2006-01-01 | S-EPMC1356344 | BioStudies
| S-EPMC5800276 | BioStudies
| S-EPMC240726 | BioStudies
| S-EPMC2663775 | BioStudies
| S-EPMC8649776 | BioStudies
| S-EPMC5461578 | BioStudies