2. Academic Validation
  3. KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells

KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells

  • bioRxiv. 2023 Sep 5:2023.09.04.556156. doi: 10.1101/2023.09.04.556156.
Mai-Uyen Nguyen 1,  Sarah Potgieter 2,  Winston Huang 1,  Julie Pfeffer 1,  Sean Woo 1,  Caifeng Zhao 3,  Matthew Lawlor 1,  Richard Yang 1,  Angela Halstead 4,  Sharon Dent 5,  José B Sáenz 6,  Haiyan Zheng 3,  Zuo-Fei Yuan 7,  Simone Sidoli 8,  Christopher E Ellison 1,  Michael Verzi 9
Affiliations

Affiliations

  • 1 Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ.
  • 2 Department of Animal Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ.
  • 3 Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ.
  • 4 Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, St. Louis, MO.
  • 5 The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 6 Division of Gastroenterology, Departments of Medicine and Molecular Cell Biology, Washington University in St. Louis, St. Louis, MO.
  • 7 St. Jude Children's Research Hospital, Memphis, TN.
  • 8 Albert Einstein College of Medicine, The Bronx, NY.
  • 9 Department of Genetics, Human Genetics Institute of New Jersey, Rutgers Cancer Institute of New Jersey, Rutgers Center for Lipid Research, Division of Environmental & Population Health Biosciences, EOHSI, Rutgers, The State University of New Jersey, Piscataway, NJ.
PMID: 37732252 DOI: 10.1101/2023.09.04.556156
Abstract

Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile Organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.

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