Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks

Amel Chaouch; Johannes Berlandi; Carol C L Chen; Felice Frey; Shireen Badini; Ashot S Harutyunyan; Xiao Chen; Brian Krug; Steven Hébert; Astrid Jeibmann; Chao Lu; Claudia L Kleinman; Martin Hasselblatt; Paul Lasko; Margret Shirinian; Nada Jabado

doi:10.1016/j.molcel.2021.10.008

Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks

Mol Cell. 2021 Dec 2;81(23):4876-4890.e7. doi: 10.1016/j.molcel.2021.10.008. Epub 2021 Nov 4.

Authors

Affiliations

¹ Department of Biology, McGill University, Montreal, QC, Canada.
² Institute of Neuropathology, University Hospital Münster, Münster, Germany.
³ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁴ Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
⁵ Department of Genetics and Development, Columbia University, New York, NY, USA.
⁶ The Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
⁷ Department of Human Genetics, McGill University, Montreal, QC, Canada; The Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
⁸ Department of Biology, McGill University, Montreal, QC, Canada; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address: [email protected].
⁹ Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. Electronic address: [email protected].
¹⁰ Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Paediatrics, McGill University and the Research Institute of the McGill University Health Center, Montreal, QC, Canada. Electronic address: [email protected].

Abstract

Histone H3.3 lysine-to-methionine substitutions K27M and K36M impair the deposition of opposing chromatin marks, H3K27me3/me2 and H3K36me3/me2. We show that these mutations induce hypotrophic and disorganized eyes in Drosophila eye primordia. Restriction of H3K27me3 spread in H3.3K27M and its redistribution in H3.3K36M result in transcriptional deregulation of PRC2-targeted eye development and of piRNA biogenesis genes, including krimp. Notably, both mutants promote redistribution of H3K36me2 away from repetitive regions into active genes, which associate with retrotransposon de-repression in eye discs. Aberrant expression of krimp represses LINE retrotransposons but does not contribute to the eye phenotype. Depletion of H3K36me2 methyltransferase ash1 in H3.3K27M, and of PRC2 component E(z) in H3.3K36M, restores the expression of eye developmental genes and normal eye growth, showing that redistribution of antagonistic marks contributes to K-to-M pathogenesis. Our results implicate a novel function for H3K36me2 and showcase convergent downstream effects of oncohistones that target opposing epigenetic marks.

Keywords: Drosophila; H3K27me3; H3K36me2; K27M; K36M; ash1; krimp; oncohistones; piRNA; transposons.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Centromere / ultrastructure
Chromatin / chemistry*
Chromatin Immunoprecipitation
Computational Biology / methods
DNA Methylation
DNA Transposable Elements*
Drosophila melanogaster
Epigenesis, Genetic
Histones / chemistry*
Histones / genetics*
Humans
Imaginal Discs / metabolism*
Lysine / chemistry
Methionine / chemistry
Mice
Microscopy, Electron, Scanning
Microscopy, Fluorescence
Mutation*
Phenotype
RNA-Seq

Substances

Chromatin
DNA Transposable Elements
Histones
Methionine
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding