先天性室间隔缺损中的一个GATA4基因新突变

目的 研究GATA4基因新突变导致先天性室间隔缺损(ventricular septal defect,VSD)的分子机制.方法 收集185例先天性VSD患者的临床资料和血标本,以200名健康者为对照.应用PCR扩增GATA4基因的全部外显子,采用双脱氧核苷链末端合成终止法对全部扩增片段进行测序以识别基因突变.克隆GATA4基因,通过定位诱变获得相应的突变体,应用脂质体将GATA4基因重组表达质粒及心房利钠肽基因启动子启动绿色荧光蛋白表达的报告载体转染HeLa细胞,应用逆转录-PCR研究GATA4基因突变对其编码的转录因子的活性的影响.结果 在1例VSD患者的GATA4基因发现1个新的杂合错义突变c.191G＞A,即第64位的密码子由GGA变为GAA,导致第64位的甘氨酸变为谷氨酸,即G64E突变.细胞表达分析显示GATA4突变G64E使转录因子的活性降低.结论 在先天性VSD患者发现GATA4新突变G64E,该突变可能通过抑制转录因子的活性而参与先天性VSD.     

Nkx2-5、GATA-4转录因子在心脏发育中的作用

心脏是胚胎发育过程中最先形成的器官。导致心脏形成和发育的确切机制目前还不清楚。转录因子以组织特异性和定量的方式调节其它器官形成和发育 ,从而在胚胎发育过程中起主要的调节作用。转录因子在心脏发育过程中可以调节心肌特异性基因的表达。     

心脏特异转录因子NKX2-5、TBX5、GATA4与先天性心脏病的研究进展

许多基因严格时空顺序的表达调控着心脏的正常发育,其中任一个基因的异常都可能导致先天性心脏病的发生。NKX2-5、TBX5、GATA4是心脏早期发育中最重要的3个转录因子,三者质或量的异常均会导致心脏畸形。大量研究提示,三者存在着复杂的相互作用,且位于许多基因的上游,可能以复合体的形式调控着心脏中许多转录因子的正确表达。本文对其特点、功能及可能的作用机制做一综述。     

Differential usage of transcriptional repressor Zeb2 enhancers distinguishes adult and embryonic hematopoiesis

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PRC2‐complex related dysfunction in overgrowth syndromes: A review of EZH2, EED,and SUZ12 and their syndromic phenotypes

The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic “writer” with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss‐of‐function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2‐associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED‐associated overgrowth (Cohen–Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.     

滋养组织中转录因子GATA3的表达及意义

目的探讨转录因子GATA3在滋养组织中的表达及其鉴别诊断价值。方法运用免疫组化EnVision法检测GATA3在91例滋养组织中的表达,包括30例正常胎盘组织、30例水泡状胎块、18例绒毛膜癌、3例胎盘部位滋养细胞肿瘤、5例胎盘部位结节及5例超常胎盘部位;同时检测30例子宫颈癌及30例子宫内膜癌中GATA3的表达。结果 GATA3在早期胎盘组织中呈弥漫强阳性,成熟绒毛中表达明显减弱,但在胎盘部位呈持续强阳性。61例滋养细胞疾病中,仅1例绒毛膜癌阴性,其余病例均为阳性;阳性细胞主要定位于细胞滋养细胞和中间型滋养细胞,合体滋养细胞基本不着色。子宫内膜癌中无GATA3阳性病例;3例子宫颈鳞状细胞癌呈弱至中等的局灶着色,子宫颈腺癌中GATA3均呈阴性。GATA3在滋养细胞病变中敏感性及特异性分别为98.36%及95.00%。结论 GATA3是滋养细胞较为敏感及特异的标志物,不能区分不同类型的滋养细胞疾病,但可鉴别滋养细胞疾病及苗勒管起源的恶性肿瘤。     

A novel polymorphic GATA site in the human IL-12Rbeta2 promoter region affects transcriptional activity

Interleukin-12 (IL-12) is a potent inducer of interferon-gamma production by T cells and is a major factor for the development of T-helper 1 (Th1) cells. It exerts its biological effects through binding to the IL-12 receptor (IL-12R), a heterodimer composed of a 1 and a beta2 subunits. The signaling beta2 chain is expressed on Th1 cells and to a lesser extent on Th0 cells, but not on Th2 cells, rendering these latter cells unresponsive to IL-12. Polymorphisms in the coding region of the IL-12Rbeta2 gene were shown to be associated with atopic disease. Here, we analyzed the 5'-regulatory region of the human IL-12Rbeta2 gene by denaturing high-performance liquid chromatography (Transgenomic WAVE system, San Jose, CA). We found five novel single-nucleotide polymorphisms (SNPs) in the proximal 1.2 kb IL-12Rbeta2 promoter region, i.e. -237C/T, -465A/G, -1023A/G, -1033T/C, and -1035A/G. SNP -465A/G is of particular interest as it determines the integrity of a GATA consensus site. By functional comparison of both -465 alleles in transient transfection assays, we show that promoter activity is increased in case of the -465G allele, disrupting the intact GATA site. Comparison of the prevalence of -465A/G SNP alleles in small cohorts of allergic asthmatic and healthy control individuals provided no evidence for an altered distribution in the asthmatic population. In conclusion, we have identified a novel polymorphic GATA site that may affect transciptional activity of the human IL-12Rbeta2 gene under GATA3-mediated, Th2-polarizing conditions.     

IRF8 deficiency induces the transcriptional,functional, and epigenetic reprogramming of cDC1 into the cDC2 lineage

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