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Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Journal of Molecular Cell Biology 2012年第2期4卷 79-87页

作者： Zhenxun Wang Deblina Chatterjee Hyun Yong Jeon Martin Akerman Matthew G.Vander Heiden Lewis C.Cantley adrian r.krainer Cold Spring Harbor Laboratory PO Box 100Cold Spring HarborNY 11724USA Watson School of Biological Sciences Cold Spring HarborNY 11724USA Graduate Program in Molecular and Cellular Biology Stony Brook UniversityStony BrookNY 11794USA Koch Institute for Integrative Cancer research at MIT CambridgeMA 02139USA Division of Signal Transduction Beth Israel Deaconess Medical Center and Department of Systems BiologyHarvard Medical SchoolBostonMA 02115USA

Alternative splicing of the pyruvate kinase M gene(PK-M)can generate the M2 isoform and promote aerobic glycolysis and tumor ***,the cancer-specific alternative splicing regulation of PK-M is not completely ***,we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10,such that exon 9 is repressed and exon 10 is activated in cancer ***,exonic,rather than intronic,cis-elements are key determinants of PK-M splicing isoform *** a systematic sub-exonic duplication approach,we identify a potent exonic splicing enhancer in exon 10,which differs from its homologous counterpart in exon 9 by only two *** identify SrSF3 as one of the cognate factors,and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose *** findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect,and also have implications for other genes with a similar pattern of alternative splicing.

关键词： alternative splicing cancer metabolism pyruvate kinase SrSF3

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Disruption of splicing-regulatory elements using CrISPr/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice

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National Science review 2020年第1期7卷 92-101页

作者： Jin-Jing Li Xiang Lin Cheng Tang Ying-Qian Lu Xinde Hu Erwei Zuo He Li Wenqin Ying Yidi Sun Lu-Lu Lai Hai-Zhu Chen Xin-Xin Guo Qi-Jie Zhang Shuang Wu Changyang Zhou Xiaowen Shen Qifang Wang Min-Ting Lin Li-Xiang Ma Ning Wang adrian r.krainer Linyu Shi Hui Yang Wan-Jin Chen Department of Neurology and Institute of Neurology The First Affiliated Hospital of Fujian Medical University Fujian Key Laboratory of Molecular Neurology Fujian Medical University Institute of Neuroscience State Key Laboratory of Neuroscience Key Laboratory of Primate Neurobiology CAS Center for Excellence in Brain Science and Intelligence Technology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Key Lab of Computational Biology CAS-MPG Partner Institute for Computational Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Anatomy Histology & Embryology Shanghai Medical College Fudan University Cold Spring Harbor Laboratory Cold Spring Harbor

We here report a genome-editing strategy to correct spinal muscular atrophy(SMA). rather than directly targeting the pathogenic exonic mutations, our strategy employed Cas9 and guide-sg rNA for the targeted disruption of intronic splicing-regulatory elements. We disrupted intronic splicing silencers(ISSs, including ISS-N1 and ISS + 100) of survival motor neuron(SMN) 2, a key modifier gene of SMA, to enhance exon 7 inclusion and full-length SMN expression in SMA iPSCs. Survival of splicing-corrected iPSC-derived motor neurons was rescued with SMN restoration. Furthermore, co-injection of Cas9 mrNA from Streptococcus pyogenes(SpCas9) or Cas9 from Staphylococcus aureus(SaCas9) alongside their corresponding sgrNAs targeting ISS-N1 into zygotes rescued 56% and 100% of severe SMA transgenic mice(Smn-/-, SMN2tg/-).The median survival of the resulting mice was extended to >400 days. Collectively, our study provides proof-of-principle for a new strategy to therapeutically intervene in SMA and other rNA-splicing-related diseases.

关键词： spinal muscular atrophy SMN2 splicing-regulatory elements CrISPr/Cas9 germline correction

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A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy

A-44G transition in SMN2 intron 6 protects patients with spi...

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中国神经科学学会第十二届全国学术会议

作者： Xingxing Wu Shu-Huei Wang Junjie Sun adrian r.krainer Yimin Hua Thomas W.Prior Jiangsu Key Laboratory of Translational research and Therapy for Neuro-PsychoDiseases The Second Affiliated Hospital of Soochow University Department of Pathology Ohio State University Cold Spring Harbor Laboratory Cold Spring Harbor Institute of Neuroscience Soochow University

Spinal muscular atrophy(SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron(SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859 G>C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44 G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6 T transition, no other changes were detected. Analyzed with minigenes, SMN1 C6 T displayed a 0% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44 G transition in intron 6. Using rNA-affinity chromatography and mass spectrometry, we further uncovered binding of the rNA-binding protein Hu r to the-44 region, where it acts as a splicing repressor. The A-44 G change markedly decreases the binding affinity of Hu r, resulting in a moderate increase in exon 7 inclusion.

关键词： SMA SMN2 copy number splicing silencer Hur rNA binding protein

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采用DNA片段编辑技术反转CTCF结合位点改变基因组拓扑结构和增强子与启动子功能

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科学新闻 2016年第1期 44-44页

作者：郭亚许泉 Daniele Canzio Jia Shou Jinhuan Li David U.Gorkin Inkyung Jung Haiyang Wu Yanan Zhai Yuanxiao Tang Yichao Lu Yonghu Wu Zhilian Jia Wei Li Michael Q.Zhang Bing ren adrian r.krainer Tom Maniatis 吴强上海交通大学上海交通大学系统生物医学研究院比较生物医学中心哈佛大学系统生物医学教育部重点实验室科技部

文章简介染色体架构蛋白CTCF和粘连蛋白复合物Cohesin在哺乳动物基因组绝缘子功能和染色质高级结构中起到关键作用。近来观察到CTCF结合位点的方向和染色质环化相关,但功能尚不清楚。为了揭示这一观察的重要性功能,本研究以原钙粘蛋白... 详细信息

文章简介染色体架构蛋白CTCF和粘连蛋白复合物Cohesin在哺乳动物基因组绝缘子功能和染色质高级结构中起到关键作用。近来观察到CTCF结合位点的方向和染色质环化相关,但功能尚不清楚。为了揭示这一观察的重要性功能,本研究以原钙粘蛋白和珠蛋白基因簇为模式基因,采用基因组DNA片段编辑技术,结合染色体构象捕获,实验证明哺乳动物基因组中CTCF结合位点的位置和相对方向,决定长距离染色质环化的特异性。反转原钙粘蛋白增强

关键词：增强子 CTCF 基因组染色体组结合位点拓扑结构数据结构 DNA

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脊髓性肌萎缩症的分子及病理机制

脊髓性肌萎缩症的分子及病理机制

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中华医学会第十八次全国神经病学学术会议

作者：孔玲玲 David Valdivia Noah Pyles Melissa Crowder rhiannon Desideri Crystal Davis Melissa Osborne Yimin Hua adrian krainer Frank rigo Frank Bennett Cathleen Lutz Kathryn J.Swodoba Tom Crawford Charlotte J.Sumner Department of Neurology Johns Hopkins University School of Medicine The Jackson Laboratory Cold Spring Harbor Laboratory Isis Pharmaceuticals Neuroscience Johns Hopkins University School of Medicine

Background Promising treatments that increase SMN expression and markedly improve disease outcomes in SMA mice are currently advancing to clinical trials in SMA *** preclinical therapeutic studies highlight the requirement for early intervention,there is little human data to guide when SMN induction may be required in human *** order to advance our understanding of human SMA,we are characterizing

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