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The histone chaperone FACT facilitates heterochromatin spreading through regulation of histone turnover and H3K9 methylation states

View ORCID ProfileMagdalena Murawska, R. A. Greenstein, View ORCID ProfileTamas Schauer, Karl C.F. Olsen, Henry Ng, View ORCID ProfileAndreas G. Ladurner, View ORCID ProfileBassem Al-Sady, View ORCID ProfileSigurd Braun
doi: https://doi.org/10.1101/2021.06.30.450523
Magdalena Murawska
1Biomedical Center, Physiological Chemistry, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
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  • For correspondence: magdalena.murawska@bmc.med.lmu.de bassem.al-sady@ucsf.edu sigurd.braun@bmc.med.lmu.de
R. A. Greenstein
2Department of Microbiology and Immunology and the George Williams Hooper Foundation, University of California San Francisco, San Francisco CA 94143, United States
3TETRAD graduate program, University of California San Francisco, San Francisco CA 94143, United States
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Tamas Schauer
4Biomedical Center, Bioinformatics Unit, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
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Karl C.F. Olsen
1Biomedical Center, Physiological Chemistry, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
5International Max Planck Research School for Molecular and Cellular Life Sciences, Planegg-Martinsried, Germany
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Henry Ng
2Department of Microbiology and Immunology and the George Williams Hooper Foundation, University of California San Francisco, San Francisco CA 94143, United States
3TETRAD graduate program, University of California San Francisco, San Francisco CA 94143, United States
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Andreas G. Ladurner
1Biomedical Center, Physiological Chemistry, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
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Bassem Al-Sady
2Department of Microbiology and Immunology and the George Williams Hooper Foundation, University of California San Francisco, San Francisco CA 94143, United States
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  • For correspondence: magdalena.murawska@bmc.med.lmu.de bassem.al-sady@ucsf.edu sigurd.braun@bmc.med.lmu.de
Sigurd Braun
1Biomedical Center, Physiological Chemistry, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
5International Max Planck Research School for Molecular and Cellular Life Sciences, Planegg-Martinsried, Germany
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  • For correspondence: magdalena.murawska@bmc.med.lmu.de bassem.al-sady@ucsf.edu sigurd.braun@bmc.med.lmu.de
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Abstract

Heterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT has been implicated in heterochromatin silencing, however, the mechanisms by which FACT engages in this process remain opaque. Here, we pin-pointed its function to the heterochromatin spreading process. FACT impairment reduces nucleation-distal H3K9me3 and HP1/Swi6 accumulation at subtelomeres and derepresses genes in the vicinity of heterochromatin boundaries. FACT promotes spreading by repressing heterochromatic histone turnover, which is crucial for the H3K9me2 to me3 transition that enables spreading. FACT mutant spreading defects are suppressed by removal of the H3K9 methylation antagonist Epe1 via nucleosome stabilization. Together, our study identifies FACT as a histone chaperone that specifically promotes heterochromatin spreading and lends support to the model that regulated histone turnover controls the propagation of epigenetic marks.

Competing Interest Statement

The authors declare a competing interest. A.G.L. is co-founder and CSO of Eisbach Bio GmbH.

Footnotes

  • ↵6 Lead contact.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 01, 2021.
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The histone chaperone FACT facilitates heterochromatin spreading through regulation of histone turnover and H3K9 methylation states
Magdalena Murawska, R. A. Greenstein, Tamas Schauer, Karl C.F. Olsen, Henry Ng, Andreas G. Ladurner, Bassem Al-Sady, Sigurd Braun
bioRxiv 2021.06.30.450523; doi: https://doi.org/10.1101/2021.06.30.450523
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The histone chaperone FACT facilitates heterochromatin spreading through regulation of histone turnover and H3K9 methylation states
Magdalena Murawska, R. A. Greenstein, Tamas Schauer, Karl C.F. Olsen, Henry Ng, Andreas G. Ladurner, Bassem Al-Sady, Sigurd Braun
bioRxiv 2021.06.30.450523; doi: https://doi.org/10.1101/2021.06.30.450523

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