Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks
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Cell Press
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. © 2021 Elsevier Inc.
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Ash1, Drosophila, H3k27me3, H3k36me2, K27m, K36m, Krimp, Oncohistones, Pirna, Transposons, Animals, Animals, genetically modified, Centromere, Chromatin, Chromatin immunoprecipitation, Computational biology, Dna methylation, Dna transposable elements, Drosophila melanogaster, Epigenesis, genetic, Histones, Humans, Imaginal discs, Lysine, Methionine, Mice, Microscopy, electron, scanning, Microscopy, fluorescence, Mutation, Phenotype, Rna-seq, Histone h3, Histone h3.3, Histone h3k27m, Histone h3k27me2, Histone h3k27me3, Histone h3k36m, Histone h3k36me2, Histone h3k36me3, Hox protein, Methyltransferase, Methyltransferase ash1, Piwi interacting rna, Polycomb repressive complex 2, Unclassified drug, Histone, Allogeneic restriction, Amino acid substitution, Animal experiment, Article, Biogenesis, Developmental gene, Down regulation, Eye development, Gene expression, Gene expression regulation, Gene mutation, Gene overexpression, Histone methylation, Imaginal disc, Long interspersed nuclear element, Nonhuman, Ommatidium, Optic disk, Pathogenesis, Photoreceptor, Protein depletion, Retroposon, Transcription regulation, Transposon, Animal, Biology, Chemistry, Fluorescence microscopy, Genetic epigenesis, Genetics, Human, Metabolism, Mouse, Procedures, Scanning electron microscopy, Transgenic animal, Ultrastructure