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Complete loss of H3K9 methylation dissolves mouse heterochromatin organization

Thomas Montavon, Nicholas Shukeir, Galina Erikson, Bettina Engist, Megumi Onishi-Seebacher, Devon Ryan, Yaarub Musa, Gerhard Mittler, Alexandra Graff Meyer, Christel Genoud and Thomas Jenuwein ()
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Thomas Montavon: Max-Planck Institute of Immunobiology and Epigenetics
Nicholas Shukeir: Max-Planck Institute of Immunobiology and Epigenetics
Galina Erikson: Max-Planck Institute of Immunobiology and Epigenetics
Bettina Engist: Max-Planck Institute of Immunobiology and Epigenetics
Megumi Onishi-Seebacher: Max-Planck Institute of Immunobiology and Epigenetics
Devon Ryan: Max-Planck Institute of Immunobiology and Epigenetics
Yaarub Musa: Max-Planck Institute of Immunobiology and Epigenetics
Gerhard Mittler: Max-Planck Institute of Immunobiology and Epigenetics
Alexandra Graff Meyer: Friedrich Miescher Institute for Biomedical Research
Christel Genoud: Friedrich Miescher Institute for Biomedical Research
Thomas Jenuwein: Max-Planck Institute of Immunobiology and Epigenetics

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp. We used mouse embryonic fibroblasts (MEFs) with a conditional mutation for Eset1 and introduced progressive deletions for the other SET domain genes by CRISPR/Cas9 technology. Compound mutant MEFs for all six SET domain lysine methyltransferase (KMT) genes lack all H3K9 methylation states, derepress nearly all families of repeat elements and display genomic instabilities. Strikingly, the 6KO H3K9 KMT MEF cells no longer maintain heterochromatin organization and have lost electron-dense heterochromatin. This is a compelling analysis of H3K9 methylation-deficient mammalian chromatin and reveals a definitive function for H3K9 methylation in protecting heterochromatin organization and genome integrity.

Date: 2021
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DOI: 10.1038/s41467-021-24532-8

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