Mason Amanda G, Garza Renee M, McCormick Mark A, Patel Bhumil, Kennedy Brian K, Pillus Lorraine, La Spada Albert R
Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Aging Cell. 2017 Aug;16(4):785-796. doi: 10.1111/acel.12611. Epub 2017 May 31.
Sgf73, a core component of SAGA, is the yeast orthologue of ataxin-7, which undergoes CAG-polyglutamine repeat expansion leading to the human neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To further define the basis for Sgf73-mediated RLS extension, we performed ChIP-Seq, identified 388 unique genomic regions occupied by Sgf73, and noted enrichment in promoters of ribosomal protein (RP)-encoding genes. Of 388 Sgf73 binding sites, 33 correspond to 5' regions of genes implicated in RLS extension, including 20 genes encoding RPs. Furthermore, half of Sgf73-occupied, RLS-linked RP genes displayed significantly reduced expression in sgf73Δ mutants, and double null strains lacking SGF73 and a Sgf73-regulated, RLS-linked RP gene exhibited no further increase in replicative lifespan. We also found that sgf73Δ mutants display altered acetylation of Ifh1, an important regulator of RP gene transcription. These findings implicate altered ribosomal protein expression in sgf73Δ yeast RLS and highlight altered acetylation as a pathway of relevance for SCA7 neurodegeneration.
Sgf73是SAGA的核心组成部分，是ataxin-7的酵母同源物，ataxin-7会发生CAG-聚谷氨酰胺重复序列扩增，导致人类神经退行性疾病7型脊髓小脑共济失调（SCA7）。缺失SGF73可显著延长酵母的复制寿命（RLS）。为了进一步确定Sgf73介导的RLS延长的基础，我们进行了染色质免疫沉淀测序（ChIP-Seq），鉴定出388个被Sgf73占据的独特基因组区域，并注意到核糖体蛋白（RP）编码基因启动子中的富集。在388个Sgf73结合位点中，33个对应于与RLS延长相关的基因的5'区域，包括20个编码RP的基因。此外，一半被Sgf73占据的、与RLS相关的RP基因在sgf73Δ突变体中表达显著降低，并且缺乏SGF73和一个受Sgf73调控的、与RLS相关的RP基因的双缺失菌株在复制寿命上没有进一步增加。我们还发现sgf73Δ突变体显示出Ifh1（RP基因转录的重要调节因子）的乙酰化改变。这些发现表明sgf73Δ酵母RLS中核糖体蛋白表达改变，并突出了乙酰化改变作为与SCA7神经退行性变相关的一条途径。
