CHD1 controls H3.3 incorporation in adult brain chromatin to maintain metabolic homeostasis and normal lifespan

Ines Schoberleitner, Ingo Bauer, Anming Huang, Evgeniya N. Andreyeva, Johanna Sebald, Katharina Pascher, Dietmar Rieder, Melanie Brunner, Valerie Podhraski, Gregor Oemer, Daniel Cázarez-García, Leila Rieder, Markus A. Keller, Robert Winkler, Dmitry Fyodorov, Alexandra Lusser

Research output: Contribution to journalArticlepeer-review

Abstract

The ATP-dependent chromatin remodeling factor CHD1 is essential for the assembly of variant histone H3.3 into paternal chromatin during sperm chromatin remodeling in fertilized eggs. It remains unclear, however, if CHD1 has a similar role in normal diploid cells. Using a specifically tailored quantitative mass spectrometry approach, we show that Chd1 disruption results in reduced H3.3 levels in heads of Chd1 mutant flies. Chd1 deletion perturbs brain chromatin structure in a similar way as H3.3 deletion and leads to global de-repression of transcription. The physiological consequences are reduced food intake, metabolic alterations, and shortened lifespan. Notably, brain-specific CHD1 expression rescues these phenotypes. We further demonstrate a strong genetic interaction between Chd1 and H3.3 chaperone Hira. Thus, our findings establish CHD1 as a factor required for the assembly of H3.3-containing chromatin in adult cells and suggest a crucial role for CHD1 in the brain as a regulator of organismal health and longevity.

Original languageEnglish (US)
Article number109769
JournalCell Reports
Volume37
Issue number1
DOIs
StatePublished - Oct 5 2021

Keywords

  • aging
  • calorie restriction
  • chronic inflammation
  • epigenetics
  • feeding behavior
  • heterochromatin
  • histone chaperone
  • longevity
  • metabolic disease
  • metabolome
  • quantitative proteomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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