ATRX limits the accessibility of histone H3-occupied HSV genomes during lytic infection.

Autor: Cabral JM; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.; Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America., Cushman CH; Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America., Sodroski CN; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.; Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America., Knipe DM; Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.; Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2021 Apr 28; Vol. 17 (4), pp. e1009567. Date of Electronic Publication: 2021 Apr 28 (Print Publication: 2021).
DOI: 10.1371/journal.ppat.1009567
Abstrakt: Histones are rapidly loaded on the HSV genome upon entry into the nucleus of human fibroblasts, but the effects of histone loading on viral replication have not been fully defined. We showed recently that ATRX is dispensable for de novo deposition of H3 to HSV genomes after nuclear entry but restricted infection through maintenance of viral heterochromatin. To further investigate the roles that ATRX and other histone H3 chaperones play in restriction of HSV, we infected human fibroblasts that were systematically depleted of nuclear H3 chaperones. We found that the ATRX/DAXX complex is unique among nuclear H3 chaperones in its capacity to restrict ICP0-null HSV infection. Only depletion of ATRX significantly alleviated restriction of viral replication. Interestingly, no individual nuclear H3 chaperone was required for deposition of H3 onto input viral genomes, suggesting that during lytic infection, H3 deposition may occur through multiple pathways. ChIP-seq for total histone H3 in control and ATRX-KO cells infected with ICP0-null HSV showed that HSV DNA is loaded with high levels of histones across the entire viral genome. Despite high levels of H3, ATAC-seq analysis revealed that HSV DNA is highly accessible, especially in regions of high GC content, and is not organized largely into ordered nucleosomes during lytic infection. ATRX reduced accessibility of viral DNA to the activity of a TN5 transposase and enhanced accumulation of viral DNA fragment sizes associated with nucleosome-like structures. Together, these findings support a model in which ATRX restricts viral infection by altering the structure of histone H3-loaded viral chromatin that reduces viral DNA accessibility for transcription. High GC rich regions of the HSV genome, especially the S component inverted repeats of the HSV-1 genome, show increased accessibility, which may lead to increased ability to transcribe the IE genes encoded in these regions during initiation of infection.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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