Histone deacetylase-1 is required for epigenome stability in Neurospora crassa
Histone deacetylase-1 is required for epigenome stability in Neurospora crassa
Ebot-Ojong, F.; Ferraro, A. R.; Kaddar, F.; Hull-Crew, C.; Scadden, A. W.; Klocko, A. D.; Lewis, Z. A.
AbstractPolycomb group (PcG) proteins form chromatin modifying complexes that control cell fate, mammalian X-chromosome inactivation, and plant vernalization. Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3) to stably repress lineage- or context-specific genes. In the model fungus Neurospora crassa, H3K27me3 patterns are modulated by the H3K36 methyltransferase ASH1 and components of constitutive heterochromatin including the H3K9me3-binding protein HETEROCHROMATIN PROTEIN 1 (HP1). Hypoacetylated histones are a defining feature of both constitutive heterochromatin and PcG-repressed chromatin, but how histone deacetylases (HDACs) contribute to normal H3K27me3 and transcriptional repression within PcG-repressed chromatin is poorly understood. We performed a genetic screen to identify HDACs required for repression of PRC2-methylated genes. In the absence of HISTONE DEACETYLASE-1 (HDA-1), PRC2-methylated genes were activated and H3K27me3 was depleted from typical PRC2-targeted regions. Regional losses of H3K27me3 were accompanied by H3K9me3 depletion, altered lysine acetylation, and aberrant deposition of both H3K27me3 and H3K36me3 in constitutive heterochromatin. CHROMODOMAIN PROTEIN-2 (CDP-2) is required to target HDA-1 to constitutive heterochromatin and was required for normal H3K27me3 patterns. Patterns of aberrant H3K27me3 were distinct in isogenic {triangleup}hda-1 strains, suggesting that loss of HDA-1 causes stochastic or progressive epigenome dysfunction. To test this, we constructed a new {triangleup}hda-1 strain and performed a laboratory evolution experiment. Loss of HDA-1 led to progressive epigenome decay over hundreds of nuclear divisions. Together, our data indicate that HDA-1 is a critical regulator of epigenome stability in N. crassa.