macroH2A1 drives nucleosome dephasing and genome instability in histone humanized yeast

In addition to replicative histones, eukaryotic genomes encode a repertoire of non-replicative variant histones, providing additional layers of structural and epigenetic regulation. Here, we systematically replace individual replicative human histones with non-replicative human variant histones usin...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2024-07, Vol.43 (7), p.114472, Article 114472
Main Authors: Haase, Max A.B., Lazar-Stefanita, Luciana, Ólafsson, Guðjón, Wudzinska, Aleksandra, Shen, Michael J., Truong, David M., Boeke, Jef D.
Format: Article
Language:English
Subjects:
chromatin
CP: Molecular biology
genome instability
histone variants
humanization
linker length
macroH2A
nucleosome
yeast
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Summary:In addition to replicative histones, eukaryotic genomes encode a repertoire of non-replicative variant histones, providing additional layers of structural and epigenetic regulation. Here, we systematically replace individual replicative human histones with non-replicative human variant histones using a histone replacement system in yeast. We show that variants H2A.J, TsH2B, and H3.5 complement their respective replicative counterparts. However, macroH2A1 fails to complement, and its overexpression is toxic in yeast, negatively interacting with yeast’s native histones and kinetochore genes. To isolate yeast with macroH2A1 chromatin, we uncouple the effects of its macro and histone fold domains, revealing that both domains suffice to override native nucleosome positioning. Furthermore, both uncoupled constructs of macroH2A1 exhibit lower nucleosome occupancy, decreased short-range chromatin interactions (
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2024.114472