欲實時把握表觀遺傳學研究最新進展和發展趨勢，請參加第四屆發育和疾病的表觀遺傳學上海國際研討會 (2018-09-18 至 2018-09-21 )，並投遞牆報摘要。
呂志民
http://faculty.mdanderson.org/Zhimin_Lu/Default.asp
MD Anderson
主題報告
2018年09月19日15:45-16:10 主題報告： ：
Metabolic regulation of gene expression
Metabolism plays an instrumental role in the regulation of gene expression via metabolic enzymes and metabolites. Metabolic enzymes and intermediates or products of metabolism, either alone or by coupling with histone modifiers, regulate transcription factor activity and histone posttranscriptional modification. Metabolic enzyme-and metabolite-mediated modulation of chromatin or activity of transcription factors regulates gene expression and thereby instrumental cellular activities.
科研成果
代表性文章：
Nature. 2017 Dec 14;552(7684):273-277. doi: 10.1038/nature25003. Epub 2017 Dec 6.
KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.
Wang Y1, Guo YR2, Liu K3, Yin Z4, Liu R1, Xia Y1, Tan L5, Yang P5, Lee JH1, Li XJ1, Hawke D6, Zheng Y1, Qian X7, Lyu J7,8, He J9, Xing D10,11,12, Tao YJ2, Lu Z1,13,14.
Histone modifications, such as the frequently occurring lysine succinylation, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
Autophagy. 2017 Oct 3;13(10):1790-1791. doi: 10.1080/15548627.2017.1349581. Epub 2017 Aug 18.
Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.
Li X1, Qian X1, Lu Z1,2,3.
Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritional stress induces nuclear translocation of ACSS2 (acyl-CoA synthetase short-chain family member 2). This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes. Knock-in of nuclear translocation-deficient or inactive ACSS2 mutants in glioblastoma cells abrogates glucose deprivation-induced lysosomal biogenesis and autophagy, reduces cell survival, inhibits brain tumorigenesis, and enhances the inhibitory effect of the glucose metabolism inhibitor 2-deoxy-d-glucose on tumor growth. These results reveal a novel biologic role for ACSS2 in recycling of nuclear acetate for histone acetylation to promote lysosomal and autophagy-related gene expression and counteract nutritional stress, highlighting the importance of ACSS2 in maintaining autophagy and lysosome-mediated cellular energy homeostasis during tumor development.
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