Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot.
Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot.
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DOI：
10.1007/s00109-019-01857-y
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
UCLA Congenital Heart Defects BioCore Faculty
中科院分区：
文献类型：
--
作者：
Zhao Y;Kang X;Gao F;Guzman A;Lau RP;Biniwale R;Wadehra M;Reemtsen B;Garg M;Halnon N;Quintero-Rivera F;Van Arsdell G;Coppola G;Nelson SF;Touma M;UCLA Congenital Heart Defects BioCore Faculty
先天性心脏缺陷（CHDs）的表型谱由遗传和环境因素共同决定。它们的相互作用是完全不同的，但可能在共同的途径上运作，如在冠心病背景下出生后心脏发育过程中的缺氧信号。法洛四联症（TOF）是最常见的紫绀型（低氧性）冠心病。然而，低氧环境对出生后TOF发病机制的影响尚不清楚。我们对来自紫绀和非紫绀TOF的右心室流出道（RVOT）样本进行了转录组分析。共表达网络分析确定了与TOF心脏临床诊断和缺氧状态特异性相关的基因模块。特别是，缺氧依赖性的肌细胞增殖诱导与e2f1介导的细胞周期调节和WNT11/RB1轴的抑制有关。在紫绀型TOF患者中，上皮间充质转化（EMT）、纤维化和肌瘤中富集的基因也受到抑制。重要的是，对缺氧调节模块的转录因子分析表明，CREB1可能是缺氧/WNT11-RB1回路的调节因子。该研究提供了与TOF表型相关的高分辨率转录组图谱，并揭示了缺氧诱导的紫绀TOF转录组重编程调控回路。缺氧诱导的心肌细胞增殖涉及WNT11-RB1轴上游CREB1活性的负向调节。
The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed transcriptome-wide analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and non-cyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11/RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provided a high-resolution landscape of transcriptome associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit of transcriptome reprograming in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis.
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影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
8
作者：
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影响因子：
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作者：
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通讯作者：
Lipovich, Leonard
DOI：
10.1136/heartjnl-2015-308348
发表时间：
2016-01
期刊：
Heart (British Cardiac Society)
影响因子：
--
作者：
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通讯作者：
Tulloh RM
影响因子：
30.8
作者：
Jin SC;Homsy J;Zaidi S;Lu Q;Morton S;DePalma SR;Zeng X;Qi H;Chang W;Sierant MC;Hung WC;Haider S;Zhang J;Knight J;Bjornson RD;Castaldi C;Tikhonoa IR;Bilguvar K;Mane SM;Sanders SJ;Mital S;Russell MW;Gaynor JW;Deanfield J;Giardini A;Porter GA Jr;Srivastava D;Lo CW;Shen Y;Watkins WS;Yandell M;Yost HJ;Tristani-Firouzi M;Newburger JW;Roberts AE;Kim R;Zhao H;Kaltman JR;Goldmuntz E;Chung WK;Seidman JG;Gelb BD;Seidman CE;Lifton RP;Brueckner M
通讯作者：
Brueckner M