A Novel HDAC Complex in the Control of Transcription and Genome Stability

The acetylation state of histones, controlled by histone acetyltransferases and deacetylases, profoundly affects DNA transcription and repair by modulating chromatin accessibility to the cellular machinery. The Schizosaccharomyces pombe HDAC Clr6 (human HDAC1) binds to different sets of proteins that define functionally distinct complexes: I, I’ and II. Here we determine the composition, architecture and functions of a new Clr6 HDAC complex, I'', delineated by the novel proteins Nts1, Mug165 and Png3. Deletion of nts1 causes increased sensitivity to genotoxins and deregulated expression of Tf2 elements, long non-coding RNA, subtelomeric and stress-related genes. Similar, but more pervasive, phenotypes are observed upon Clr6 inactivation, supporting the designation of complex I'' as a mediator of a key subset of Clr6 functions. We also reveal that with the exception of Tf2 elements, Clr6 I''-regulated loci and its genome-wide loading sites do not correlate. Instead, Nts1 loads at genes that are expressed in mid-meiosis, following oxidative stress, or are periodically expressed. Collective data suggest that Clr6 I'' has (i) indirect effects on gene expression, conceivably by mediating higher-order chromatin organization of sub-telomeres and Tf2 elements, and (ii) direct effects on the transcription of specific genes in response to certain cellular or environmental stimuli. Identification of the genome binindg sites for Nts1 (SPCC24B10.19C) in Schizosaccharomyces pombe