macroH2A1 drives nucleosome dephasing and genome instability in histone humanized yeast

Max A.B. Haase, Luciana Lazar-Stefanita, Guðjón Ólafsson, Aleksandra Wudzinska, Michael J. Shen, David M. Truong, Jef D. Boeke

Research output: Contribution to journalArticlepeer-review

Abstract

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 (<20 kb), disrupted centromeric clustering, and increased chromosome instability. Our observations demonstrate that lack of a canonical histone H2A dramatically alters chromatin organization in yeast, leading to genome instability and substantial fitness defects.

Original languageEnglish (US)
Article number114472
JournalCell Reports
Volume43
Issue number7
DOIs
StatePublished - Jul 23 2024

Keywords

  • CP: Molecular biology
  • chromatin
  • genome instability
  • histone variants
  • humanization
  • linker length
  • macroH2A
  • nucleosome
  • yeast

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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