GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.
GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.
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DOI：
10.7554/elife.53278
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发表时间：
2020-10-15
期刊：
影响因子：
7.7
通讯作者：
Pediatric Cardiac Genomics Consortium
中科院分区：
文献类型：
--
作者：
Sharma A;Wasson LK;Willcox JA;Morton SU;Gorham JM;DeLaughter DM;Neyazi M;Schmid M;Agarwal R;Jang MY;Toepfer CN;Ward T;Kim Y;Pereira AC;DePalma SR;Tai A;Kim S;Conner D;Bernstein D;Gelb BD;Chung WK;Goldmuntz E;Porter G;Tristani-Firouzi M;Srivastava D;Seidman JG;Seidman CE;Pediatric Cardiac Genomics Consortium
受损的GATA6变异体会导致心脏流出道缺陷，有时还会伴有胰腺和横隔膜畸形。为了确定这些不同发育缺陷的分子机制，我们研究了同基因人诱导的多能干细胞在心肌细胞分化过程中对GATA6功能丧失(LoF)和错义变体的转录和表观遗传学反应。我们表明GATA6是心脏发育的先驱因子，调节SMYD1激活HAND2，KDR与HAND2一起协调流出道的形成。Lof变异体干扰心脏基因和指导PDX1表达和胰腺发育的内胚层谱系基因。值得注意的是，与心脏外畸形高度相关的外显子4 GATA6错义变体导致了异位先锋活动，显著降低了GATA4、FOXA1/2和PDX1的表达，并增加了促进横隔膜发育的正常维甲酸信号。这些异常的表观遗传和转录特征阐明了心血管畸形、胰腺和横隔膜发育不良的分子机制，这些机制发生在具有不同GATA6变异的患者中。
Damaging GATA6 variants cause cardiac outflow tract defects, sometimes with pancreatic and diaphragmic malformations. To define molecular mechanisms for these diverse developmental defects, we studied transcriptional and epigenetic responses to GATA6 loss of function (LoF) and missense variants during cardiomyocyte differentiation of isogenic human induced pluripotent stem cells. We show that GATA6 is a pioneer factor in cardiac development, regulating SMYD1 that activates HAND2, and KDR that with HAND2 orchestrates outflow tract formation. LoF variants perturbed cardiac genes and also endoderm lineage genes that direct PDX1 expression and pancreatic development. Remarkably, an exon 4 GATA6 missense variant, highly associated with extra-cardiac malformations, caused ectopic pioneer activities, profoundly diminishing GATA4, FOXA1/2, and PDX1 expression and increasing normal retinoic acid signaling that promotes diaphragm development. These aberrant epigenetic and transcriptional signatures illuminate the molecular mechanisms for cardiovascular malformations, pancreas and diaphragm dysgenesis that arise in patients with distinct GATA6 variants.