The role of Sgf73 occupancy
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE76461 | GEO | 2017/06/12
SECONDARY ACCESSION(S): PRJNA307564
REPOSITORIES: GEO
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Project description:Spinocerebellar Ataxia Type 7 (SCA7) belonging to ADCAs is pathomechanistically related to a group of polyglutamine expansion disorders. SCA7 affects primarily brainstem, retina and cerebellum. The distinctive feature of SCA7 among ADCAs is a progressive visual impairment due to a cone-rod photoreceptor dystrophy. Ultrastructural analysis of SCA7 mouse models revealed that photoreceptors progressively lose their outer segments, a structure essential for phototransduction, which requires daily renewal. The lack of outer segment renewal correlates with decreased expression of photoreceptor-specific genes, suggesting that progressive breakdown of photoreceptor cell identity accounts for SCA7 retinopathy. SCA7 is due to a polyglutamine expansion in ATXN7, a component of the multiprotein SPT-ADA-GCN5 Acetyltransferase (SAGA) complex, a highly conserved coactivator of transcription. SAGA harbors two chromatin remodeling activities: acetylation and deubiquitynation of histones crucial for transcription initiation and elongation. The role of SAGA in SCA7 pathogenesis and the tissue specific genetic breakdown remains to be elucidated. We addressed this issue using our new SCA7 knock-in mouse model (SCA7140Q/140Q), which recapitulates cardinal features of SCA7. Using ChIP-seq approach, we confirmed the general decrease of H3K9ac in most gene promoters in SCA7 retina, which alone cannot explain the specific gene deregulation. Interestingly, we discovered that photoreceptor identity genes, which are strongly downregulated in SCA7, harbor an unusual broad profile of H3K9ac that encompasses the entire gene. We further show that H3K9ac broad profiles at photoreceptor gene loci coincide with the presence of a broad H3K27ac, a signature of superenhancers. Furthermore, using vicinity criteria we identified enhancer RNAs (eRNAs), annotated to the photoreceptor identity genes possessing an atypical H3K9ac/H3K27ac enhancer signature. Finally, we found a synchronized expression of eRNAs and photoreceptor identity genes during retinal development, suggesting a regulatory role of these eRNAs. The decreased eRNA levels on hypoacetylated loci in the retina correlate with the downregulation of photoreceptor identity genes in symptomatic but not in pre-symptomatic SCA7 mice.
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Project description:Dietary restriction (DR) is the best-characterized intervention for slowing aging, and reduced signaling through the target of rapamycin (TOR) kinase is believed to be one of the key mechanisms by which DR extends life span in organisms from yeast to mammals. Here we describe a role for nuclear sequestration of tRNA in yeast replicative life span (RLS) extension from DR. DR causes the nuclear tRNA exporter Los1 to become depleted from the nucleus by a mechanism that requires the DNA damage response factor Rad53, and deletion of LOS1 or overexpression of RAD53 is sufficient to extend RLS. We further report that activation of the nitrogen responsive transcription factor Gln3 is the primary mechanism by which DR extends RLS. Gln3 is activated by both branches of the DR response and is required for life span extension. Overexpression of Gln3 extends RLS by approximately 50%.
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