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

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. [Display omitted] • Loss of chromatin assembly factor CHD1 reduces H3.3 levels in brain chromatin • Chd1 deletion perturbs global chromatin organization similar to H3.3 deletion • Chd1 deletion causes global upregulation of transcription in fly heads • Brain-specific roles of CHD1 are required for metabolic control and healthy lifespan In postmitotic brain cells, histones lost during transcription must be replenished by replication-independent mechanisms. Schoberleitner et al. show that the chromatin remodeling factor CHD1 is involved in this process. CHD1 loss results in reduced histone H3.3 levels, global chromatin perturbation, transcriptional dysregulation, and defects in feeding behavior, metabolism, and lifespan. [ABSTRACT FROM AUTHOR]