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Three-dimensional genome architectural CCCTC-binding factor makes choice in duplicated enhancers at Pcdhα locus

Science China(Life Sciences) 2020年第6期63卷 835-844页

作者： Yonghu Wu zhilian jia Xiao Ge Qiang Wu Center for Comparative Biomedicine MOE Key Lab of Systems BiomedicineState Key Lab of Oncogenes and Related GenesShanghai Cancer InstituteJoint International Research Laboratory of Metabolic&Developmental SciencesInstitute of Systems BiomedicineXin Hua HospitalShanghai Jiao Tong UniversityShanghai 200240China

During development, gene expression is spatiotemporally regulated by long-distance chromatin interactions between distal enhancers and target promoters. However, how specificity of the interactions between enhancers and promoters is achieved remains largely unknown. As there are far more enhancers than promoters in mammalian genomes, the complexities of enhancer choice during gene regulation remain obscure. CTCF, the CCCTC-binding factor that directionally binds to a vast range of genomic sites known as CBSs(CTCF-binding sites), mediates oriented chromatin looping between a substantial set of distal enhancers and target promoters. To investigate mechanisms by which CTCF engages in enhancer choice, we used CRISPR/Cas9-based DNA-fragment editing to duplicate CBS-containing enhancers and promoters in the native genomic locus of the clustered Pcdhα genes. We found that the promoter is regulated by the proximal one among duplicated enhancers and that this choice is dependent on CTCF-mediated directional enhancer-promoter looping. In addition, gene expression is unaltered upon the switch of enhancers. Moreover, after promoter duplication, only the proximal promoter is chosen by CTCF-mediated directional chromatin looping to contact with the distal enhancer. Finally, we demonstrated that both enhancer activation and chromatin looping with the promoter are essential for gene expression. These findings have important implications regarding the role of CTCF in specific interactions between enhancers and promoters as well as developmental regulation of gene expression by enhancer switching.

关键词： enhancer duplication promoter selection enhancer choice CTCF protocadherin chromatin looping

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Genetic evidence for asymmetric blocking of higher-order chromatin structure by CTCF/cohesin

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Protein & Cell 2019年第12期10卷 914-920页

作者： Yujia Lu jia Shou zhilian jia Yonghu Wu Jinhuan Li Ya Guo Qiang Wu MOE Key Lab of Systems Biomedicine Center for Comparative BiomedicineState Key Lab of Oncogenes and Related GenesShanghai Cancer InstituteJoint International Research Laboratory of Metabolic&Developmental SciencesInstitute of Systems BiomedicineXin Hua HospitalShanghai Jiao Tong UniversityShanghai 200240China Present address:Ming Wai Lau Centre for Reparative Medicine Karolinska InstitutetHong KongChina MRC London Institute of Medical Sciences Imperial College LondonLondon W120NNUK

Dear Editor,Similar to higher-order folding of polypeptide chains into functional proteins,linear DNA molecules are spatially folded in a hierarchical and dynamic manner into three-dimensional(3D)functional chromatin structures in eukaryotic nuclei(Huang and Wu,2016;Rowley and Corces,2018).This dynamic folding is closely related to many nuclear processes such as DNA replication and repair,chromosomal translocation,recombination,and segregation,as well as RNA transcription,splicing,and transport.In particular,dynamic long-distance chromatin looping interactions,which result in close spatial contacts between distal enhancers and target promoters,are thought to play a role in controlling precise spatiotemporal as well as cell-type specific gene expression during animal development(Rowley and Corces,2018).Mammalian genomes contain numerous noncoding regulatory elements that regulate these dynamic long-distance chromatin looping interactions.

关键词： asymmetric precise chains

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Efficient inversions and duplications of mammalian regulatory DNA elements and gene clusters by CRISPR/Cas9

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分子细胞生物学报:英文版 2015年第4期7卷 284-298页

作者： Jinhuan Li jia Shou YaGuo Yuanxiao Tang YonghuWu zhilian jia Yanan Zhai Zhifeng Chen Quan Xu Qiang Wu Key Laboratory of Systems Biomedicine(Ministry of Education) Center for Comparative BiomedicineInstitute of Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of EducationBio-X CenterSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China Collaborative Innovation Center of Systems Biomedicine Shanghai Jiao Tong University School of MedicineShanghai 200240China

The human genome contains millions of DNA regulatory elements and a large number of gene clusters,most of which have not been tested experimentally.The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease 9(Cas9)programed with a synthetic single-guide RNA(sgRNA)emerges as a method for genome editing in virtually any organisms.Here we report that targeted DNA fragment inversions and duplications could easily be achieved in human and mouse genomes by CRISPR with two sgRNAs.Specifically,we found that,in cultured human cells and mice,efficient precise inversions of DNA fragments ranging in size froma few tens of bp to hundreds of kb could be generated.In addition,DNA fragment duplications and deletions could also be generated by CRISPR through trans-allelic recombination between the Cas9-induced double-strand breaks(DSBs)on two homologous chromosomes(chromatids).Moreover,junctions of combinatorial inversions and duplications of the protocadherin(Pcdh)gene clusters induced by Cas9 with four sgRNAs could be detected.In mice,we obtained founders with alleles of precise inversions,duplications,and deletions of DNA fragments of variable sizes by CRISPR.Interestingly,we found that very efficient inversions were mediated by microhomology-mediated end joining(MMEJ)through short inverted repeats.We showed for the first time that DNA fragment inversions could be transmitted through germlines in mice.Finally,we applied this CRISPR method to a regulatory element of the Pcdha cluster and found a new role in the regulation of members of the Pcdhg cluster.This simple and efficient method should be useful in manipulating mammalian genomes to study millions of regulatory DNA elements as well as vast numbers of gene clusters.

关键词： DNA regulatory element inversion duplication deletion CRISPR/Cas9 enhancer genome manipulation gene cluster

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Wiring the Brain by Clustered Protocadherin Neural Codes

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Neuroscience Bulletin 2021年第1期37卷 117-131页

作者： Qiang Wu zhilian jia1 Center for Comparative Biomedicine Ministry of Education Key Lab of Systems BiomedicineState Key Laboratory of Oncogenes and Related GenesJoint International Research Laboratory of Metabolic and Developmental SciencesInstitute of Systems BiomedicineXinhua HospitalSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China

There are more than a thousand trillion specific synaptic connections in the human brain and over a million new specific connections are formed every second during the early years of life. The assembly of these staggeringly complex neuronal circuits requires specific cell-surface molecular tags to endow each neuron with a unique identity code to discriminate self from non-self. The clustered protocadherin(Pcdh) genes, which encode a tremendous diversity of cell-surface assemblies, are candidates for neuronal identity tags. We describe the adaptive evolution,genomic structure, and regulation of expression of the clustered Pcdhs. We specifically focus on the emerging3-D architectural and biophysical mechanisms that generate an enormous number of diverse cell-surface Pcdhs as neural codes in the brain.

关键词： Clustered protocadherins Genome architecture Neuronal identity Adhesion specificity Self-avoidance Cell recognition

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RFX5调控原钙粘蛋白α基因簇的表达

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遗传 2020年第8期42卷 760-774页

作者：王娜甲芝莲吴强上海交通大学系统生物医学研究院比较生物医学研究中心系统生物医学教育部重点实验室上海200240

基因的表达调控与基因组在细胞核内的三维空间架构相辅相成,原钙粘蛋白(protocadherin,Pcdh)基因簇在大脑发育中起到关键作用,可以作为研究基因表达调控机制的模式基因。转录因子RFX5(regulatory factor x 5)是翼螺旋家族(winged HLH fa... 详细信息

基因的表达调控与基因组在细胞核内的三维空间架构相辅相成,原钙粘蛋白(protocadherin,Pcdh)基因簇在大脑发育中起到关键作用,可以作为研究基因表达调控机制的模式基因。转录因子RFX5(regulatory factor x 5)是翼螺旋家族(winged HLH family)的成员,其蛋白由寡聚化结构域、DNA结合域、螺旋结构域和激活域组成,在调控免疫系统的主要组织相容性复合物Ⅱ类(major histocompatibility complex classⅡ,MHCⅡ)的表达中起着至关重要的作用。本研究发现RFX5与CTCF在全基因组上结合的位点有部分重叠,利用CRISPR/Cas9 DNA大片段编辑技术,构建了RFX5基因缺失的HEC-1-B细胞系。通过RNA-seq实验,发现RFX5敲除能够显著升高Pcdhα6、Pcdhα12、Pcdhαc2的表达水平。通过ChIP-nexus实验,发现敲除RFX5导致染色质架构蛋白CTCF和cohesin在原钙粘蛋白α基因簇处的结合增加。最后,染色质构象捕获QHR-4C实验发现Pcdhα6、Pcdhα12启动子与远端增强子HS5-1的染色质远距离相互作用增强。上述研究表明RFX5蛋白可能通过调控染色质高级结构影响原钙粘蛋白α基因簇的表达,为未来进一步探索RFX5的功能提供了参考。

关键词： RFX5 Pcdh CTCF cohesin CRISPR/Cas9

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公共服务供给机制创新研究——兼评事业单位改革

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中国行政管理 2009年第4期 77-81页

作者：贾智莲孔春梅内蒙古财经学院财政税务学院财政系武汉大学经管学院博士研究生武汉430072 内蒙古财经学院公共管理系主任教授呼和浩特010051

公共服务供给机制的创新不仅涉及到事业单位改革,也是财政公共化进程的助推器。前期事业单位的改革过分强调"减负"和效率而偏离了公平的目标,导致基本公共服务供给不足。这其中既有政府体制的原因,也有供给制度设计的原因。事业单位改... 详细信息

公共服务供给机制的创新不仅涉及到事业单位改革,也是财政公共化进程的助推器。前期事业单位的改革过分强调"减负"和效率而偏离了公平的目标,导致基本公共服务供给不足。这其中既有政府体制的原因,也有供给制度设计的原因。事业单位改革在追求效率的同时,也要受到基本公共服务均等化目标的约束。政府在基本公共服务供给方面应承担主要责任,同时鼓励市场力量和社会力量介入,从而形成多元化的供给体系。本文尝试从兼顾效率与公平的角度对公共服务供给制度的设计、运作方式提出参考意见。

关键词：公共服务供给机制事业单位改革效率基本公共服务均等化

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财政学学科基础的多元化与课程体系的拓展

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内蒙古财经学院学报（综合版） 2009年第4期7卷 40-45页

作者：贾智莲内蒙古财经学院财政税务学院内蒙古呼和浩特010051

体制转轨与经济学转型要求财政学在现代经济学的框架内重新确立研究对象,选择科学的研究方法,建立科学的理论体系。高等学校财政学专业课程体系设计是一个能够体现财政学转型的窗口。我们选择国内36所高校财政学专业本科培养方案作为样... 详细信息

体制转轨与经济学转型要求财政学在现代经济学的框架内重新确立研究对象,选择科学的研究方法,建立科学的理论体系。高等学校财政学专业课程体系设计是一个能够体现财政学转型的窗口。我们选择国内36所高校财政学专业本科培养方案作为样本,对其专业课程的设置进行统计与分析,从中梳理现代财政学在中国发展的脉络与趋势。研究结果表明:现代财政学发展呈现的种种特点在财政学专业课程的设置中已得到较为充分的体现,以经济学为主、兼有管理学的学科基础课体系已基本形成,数学开始在学科基础课中分得一席之地;以政府预算、税收、财政支出类课程为主的专业核心课程框架已初具雏形。

关键词：体制转轨财政学转型专业课程设置

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N-WASP通过polyPro和VCA结构域调控大脑皮层神经元迁移

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遗传 2018年第5期40卷 390-401页

作者：沈秀莲逯宜超甲芝莲吴强上海交通大学系统生物医学研究院比较生物医学研究中心系统生物医学教育部重点实验室上海200240

在大脑皮层发育过程中,神经元迁移是一个动态的复杂过程,与细胞骨架构建和重塑的调控息息相关。N-WASP蛋白是Wiskott-Aldrich综合征蛋白家族(WASP-WAVE family)的一个重要成员,又名WAS-like蛋白(WASL),直接参与细胞骨架中肌动蛋白丝状... 详细信息

在大脑皮层发育过程中,神经元迁移是一个动态的复杂过程,与细胞骨架构建和重塑的调控息息相关。N-WASP蛋白是Wiskott-Aldrich综合征蛋白家族(WASP-WAVE family)的一个重要成员,又名WAS-like蛋白(WASL),直接参与细胞骨架中肌动蛋白丝状分支的动态调控。本研究通过蛋白免疫印迹检测发现N-WASP表达于小鼠胚胎发育时期(E12.5~E18.5)的大脑皮层中,并且其表达水平随着发育逐渐降低。利用在体子宫内胚胎电转实验,结果发现过表达或者敲低N-WASP均会造成不同程度的大脑皮层神经元迁移障碍,说明N-WASP在大脑皮层神经元迁移中起到关键作用。N-WASP蛋白主要包含4个结构域:WH1、GBD、poly Pro和VCA。为进一步研究N-WASP各结构域在神经元迁移中的调控功能,设计了一系列的显性负性突变实验。通过过表达结构域删除的N-WASP蛋白,发现(35)poly Pro、(35)VCA和(35)WH1均能造成神经元迁移障碍。但是,过表达不能结合Cdc42的N-WASP蛋白(H208D突变体)却不能造成明显的神经元迁移障碍。另外,单独过表达N-WASP的结构域poly Pro或VCA能够造成神经元迁移障碍,而过表达WH1结构域却不能影响迁移。最后,通过过表达poly Pro和VCA结构域同时删除的N-WASP(WH1-GBD),发现WH1-GBD结构域对神经元迁移没有明显影响。上述结果表明N-WASP蛋白主要是通过poly Pro和VCA两个结构域调控大脑皮层神经元的迁移过程。

关键词：大脑皮层神经元迁移 N-WASP 子宫内胚胎电转技术肌动蛋白细胞骨架动态

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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

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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Clinical Study on Fuzi Lizhong Pill in Treating Salivation after Taking Clozapine for Schizophrenia

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Medicinal Plant 2022年第4期13卷 53-56,60页

作者： Tiancheng jia Zhe HONG zhilian PI Chunhe MA Department of Psychiatry Fourth People s Hospital of Jiande CityJiande 311612China

[Objectives]To observe the clinical effect of Fuzi Lizhong pills for salivation after taking clozapine in schizophrenia.[Methods]A total of 45 cases of schizophrenia patients with salivation after taking clozapine only were selected as the study subjects and randomly divided into two groups according to enrollment order.The control group(22 cases)was treated with propantheline bromide tablets and the treatment group(23 cases)were treated with Fuzi Lizhong pills combined with propantheline bromide tablets.Clinical effects and adverse reactions were compared between the two groups.Chinese medicine syndrome scores,scores of severe degree of salivation and levels of serum cholinesterase were compared between the two groups before treatment,after one-week treatment and after two-week treatment.[Results]The total clinical effective rate was 86.96%in the treatment group,higher than that of 59.09%in the control group(P0.05).[Conclusions]Fuzi Lizhong pills combined with propantheline bromide tablets can improve clin

关键词： Schizophrenia Clozapine Salivation Fuzi Lizhong pill TCM syndrome score Safety

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