@article{c1da563e65fe4b00952750e4d9464054,
title = "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. 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.",
keywords = "aging, calorie restriction, chronic inflammation, epigenetics, feeding behavior, heterochromatin, histone chaperone, longevity, metabolic disease, metabolome, quantitative proteomics",
author = "Ines Schoberleitner and Ingo Bauer and Anming Huang and Andreyeva, {Evgeniya N.} and Johanna Sebald and Katharina Pascher and Dietmar Rieder and Melanie Brunner and Valerie Podhraski and Gregor Oemer and Daniel C{\'a}zarez-Garc{\'i}a and Leila Rieder and Keller, {Markus A.} and Robert Winkler and Fyodorov, {Dmitry V.} and Alexandra Lusser",
note = "Funding Information: We thank Konrad Basler, Kweon Yu and Benjamin Loppin for the gift of fly strains. We appreciate the help with methods and techniques by Gabriele Salcher-Scheran, Alexandra Wille, Carla Margulies, Sina Kunz, Dominik Br{\"u}ck, and Nico Wahl, and we are grateful to Peter Loidl and Simone Sidoli for critically reading the manuscript and helpful comments. Research on this project was funded by the Austrian Science Fund (FWF) (P31377-B30 to A.L.), the NIH (GM074233 to D.V.F.), and the Consejo Nacional de Ciencia y Tecnolog{\'i}a (CONACyT) Mexico (FRONTERAS 2015-2/814 and CONACyT-DFG 2016/277850 to R.W. and D.C.G. [Scholarship]). I.S. J.S. and A.L. conceived the project and designed the experiments. I.S. A.H. J.S. K.P. and V.P. performed phenotype characterization experiments. I.B. D.R. and L.R. analyzed NGS data. G.O. D.C.G. M.A.K. and R.W. performed metabolite mass spec experiments and data analysis. M.B. isolated histones. E.N.A. and D.V.F. developed H3.3 quantification by MRM-HR. A.L. performed ATAC-seq experiments. A.L. D.V.F. and I.S. analyzed the data and wrote the manuscript with help from I.B. M.A.K. R.K. and E.N.A. The authors declare no competing interests. Funding Information: We thank Konrad Basler, Kweon Yu and Benjamin Loppin for the gift of fly strains. We appreciate the help with methods and techniques by Gabriele Salcher-Scheran, Alexandra Wille, Carla Margulies, Sina Kunz, Dominik Br{\"u}ck, and Nico Wahl, and we are grateful to Peter Loidl and Simone Sidoli for critically reading the manuscript and helpful comments. Research on this project was funded by the Austrian Science Fund (FWF) ( P31377-B30 to A.L.), the NIH ( GM074233 to D.V.F.), and the Consejo Nacional de Ciencia y Tecnolog{\'i}a (CONACyT) Mexico ( FRONTERAS 2015-2/814 and CONACyT-DFG 2016/277850 to R.W. and D.C.G. [Scholarship]). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = oct,
day = "5",
doi = "10.1016/j.celrep.2021.109769",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}