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Series GSE199946 Query DataSets for GSE199946
Status Public on Aug 08, 2023
Title A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary During HIV infection, a latent viral reservoir is formed that persists during antiretroviral therapy (ART) and is maintained by a heritable state of transcriptional repression. Recent findings indicate that much of the reservoir originates from infections occurring in the weeks near the time of ART initiation, raising the important possibility that interventions during this period might prevent reservoir seeding and substantially reduce reservoir size. Based on this concept, we tested the ability of compounds that target epigenetic machinery to prevent the establishment of latent HIV infection in primary CD4 T cells. We identified class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention, an activity distinct from latency reversal. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression, even after HDACi withdrawal, and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to a striking change in the memory subset distribution indicating reprogramming of cell identity. Through knockout of individual HDACs and use of HDAC-selective inhibitors, we determined that HDAC1 and HDAC3 play crucial and distinct roles in proviral silencing initiation. Overall, this work indicates that a network of HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus. Epigenetic reprogramming by clinical targeting of HDACs during ART initiation may represent a novel way to prevent seeding of the HIV reservoir in vivo
 
Overall design CUT&RUN profiling of H3K4me3, H3K27ac, H3K9ac, H3K9me3 and H3K27me3 histone marks in infected cells that had been cultured with or without vorinostat (SAHA). We similarly profiled total RNA Polymerase II (RPD1 subunit, tPol2) and RNA Polymerase II phosphorylated on Ser 2 of the heptameric repeat region (P-S2, Pol2s2)
 
Contributor(s) Simon JM, Peterson JJ, Browne EP
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Submission date Apr 01, 2022
Last update date Aug 09, 2023
Contact name Jeremy Simon
E-mail(s) jsimon@ds.dfci.harvard.edu, jeremy_simon@med.unc.edu
Organization name Dana-Farber Cancer Institute
Department Department of Data Science
Street address 450 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (45)
GSM5994373 CD4_HIVdelta6_SAHA_H3K27ac_CUTRUN_Rep2
GSM5994374 CD4_HIVdelta6_SAHA_H3K27ac_CUTRUN_Rep3
GSM5994375 CD4_HIVdelta6_SAHA_H3K27me3_CUTRUN_Rep1
Relations
BioProject PRJNA822299

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE199946_HIV_p379delta6.fasta.gz 3.0 Kb (ftp)(http) FASTA
GSE199946_HIV_p379delta6.gtf.gz 514 b (ftp)(http) GTF
GSE199946_RAW.tar 8.3 Gb (http)(custom) TAR (of BW)
GSE199946_eColi_K12.fa.gz 1.4 Mb (ftp)(http) FA
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
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