CHD1 Controls H3.3 Incorporation in Adult Brain Chromatin to Maintain Metabolic Homeostasis and Normal Lifespan

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. However, it remains unclear if CHD1 has a similar role in normal diploid cells. Here we show that CHD1 indeed contributes to H3.3 incorporation into adult chromosomes, and we report severe biological consequences for organismal health that result from the loss of CHD1. Using a specifically tailored quantitative mass spectrometry approach, we find that Chd1 disruption in Drosophila melanogaster results in a striking reduction of relative H3.3 levels in heads of Chd1-mutant flies. Absence of CHD1 causes shortened lifespan, reduced food intake, metabolic alterations and leads to a global de-repression of transcription in the brain. Notably, ectopic brain-specific expression of CHD1 fully rescues these phenotypes. 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 postmitotic brain cells as a regulator of organismal health and longevity.