Retinoic acid inhibition of chromatin remodeling at the human immunodeficiency virus type 1 promoter. Uncoupling of histone acetylation and chromatin remodeling.
All-trans retinoic acid (RA) represses HIV-1 transcription and replication in cultured monocytic cells and in primary monocyte-derived macrophages. Here we examine the role of histone acetylation and chromatin remodeling in RA-mediated repression. RA pretreatment of latently infected U1 promonocytes inhibits HIV-1 expression in response to the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). TSA is thought to activate HIV-1 transcription by inducing histone hyperacetylation within a regulatory nucleosome, nuc-1, positioned immediately downstream from the transcription start site. Acetylation of nuc-1 is thought to be a critical step in activation that precedes nuc-1 remodeling and, subsequently, transcriptional initiation. Here we demonstrate that TSA treatment induces H3 and H4 hyperacetylation and nuc-1 remodeling. Although RA pretreatment inhibits nuc-1 remodeling and HIV-1 transcription, it has no effect on histone acetylation. This suggests that acetylation and remodeling are not obligatorily coupled. We also show that growth of U1 cells in retinoid-deficient medium induces nuc-1 remodeling and HIV-1 expression but does not induce histone hyperacetylation. These findings suggest that remodeling, not histone hyperacetylation, is the limiting step in transcriptional activation in these cells. Together, these data suggest that RA signaling maintains the chromatin structure of the HIV-1 promoter in a transcriptionally non-permissive state that may contribute to the establishment of latency in monocyte/macrophages.
Department of Microbiology, Boston University School of Medicine, Massachusetts 02118, USA.
Heather L B
HL
Kiefer
Timothy M
TM
Hanley
Jennifer E
JE
Marcello
A G
AG
Karthik
Gregory A
GA
Viglianti
D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure*; D004797:Enzyme-Linked Immunosorbent Assay; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000821:virology; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology
D002843:Chromatin; D016655:HIV Core Protein p24; D014212:Tretinoin