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PNAS Papers on Yeast Gene Silencing, Zika Virus Inhibition, Immunoglobulin Hypermutation

Editor's Note: Some of the articles described below are not yet available at the PNAS site but are scheduled to be posted this week.

University of California, Santa Cruz, researchers consider ties between histone H4K16 acetylation marks, Sir repressor protein binding, and gene silencing in the Saccharomyces cerevisiae yeast model organism. Using quantitative H4K16 acetylation assays, the team found that gene silencing was lost when between half and three-quarters of unacetylated nucleosomes typically bound by Sir proteins were replaced with an acetyl-mimicking H4K16Q mutant. Likewise, gene silencing could be loosened by dialing down Sir2 or Sir3 copy numbers, while lower-than-usual acetyltransferase enzyme levels led to enhanced gene silencing. From these and other results, the authors suggest that a "mere two- to threefold change in the levels of histone marks and specific Sir proteins can affect the stability of the silent state of a large chromatin domain."

A team from the University of Texas Southwestern Medical Center describes a potential neuroprotective role for the interferon-stimulated gene SHFL in a mouse model of Zika virus (ZIKV) infection. Based on their interferon-stimulated gene expression screening experiments, the researchers saw signs that the Shiftless protein encoded by SHFL can inhibit ZIKV and other positive-stranded RNA flaviviruses, while follow-up analyses in mice missing Shfl suggest it can tamp down related neurological symptoms involving type I interferon immune responses, coinciding with longer survival. "Notably, Shfl was uniquely required for controlling replication in the brain and spinal cord, demonstrating an unappreciated neuroprotective role for this effector in vivo," they report, noting that "SHFL is a key antiviral effector that specifically inhibits flavivirus genome replication, and Shfl protects mice from Zika virus-induced neuropathogenesis."

Investigators at the Albert Einstein College of Medicine and Stony Brook University describe a role for the histone H3.3 chaperone HIRA in human B cell immunoglobulin heavy chain V mutations. The team's B cell line experiments suggest that somatic hypermutation levels decline significantly across immunoglobulin variable regions in the absence of HIRA, as do several active transcription contributors. The authors suggest these and other findings from the analyses "reveal an unrecognized role of HIRA and the H3.3K36me3 modification in [somatic hypermutation] and extend our knowledge of how transcription-associated chromatin structure and accessibility contribute to [somatic hypermutation] in human B cells."