Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition.
Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition.
复制标题
DOI：
10.1007/s00109-020-01933-8
复制
发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Touma M
中科院分区：
文献类型：
--
作者：
Zhao Y;Kang X;Barsegian A;He J;Guzman A;Lau RP;Biniwale R;Wadhra M;Reemtsen B;Garg M;Halnon N;Quintero-Rivera F;Grody WW;UCLA Congenital Heart Defects BioCore Faculty;Van Arsdell G;Nelson SF;Touma M
室特异性和时间调节的围产期心脏生长和成熟对于心脏的功能适应是至关重要的，并且可以响应于围产期应激而显著改变，例如全身性缺氧（低氧血症），导致显著的病理学，甚至死亡。了解新生儿心腔对低氧血症的转录调控对于开发紫绀型先天性心脏病（CHD）婴儿的心室特异性治疗是必要的。我们试图确定低氧血症围产期循环过渡期间的室特异性转录组编程。我们对出生后第3天（P3）暴露于围产期低氧血症的小鼠心脏的右心室（RV）和左心室（LV）进行了全转录组分析。低氧血症降低了RV和LV之间的基线差异，导致心室模式（AVP）显著减弱，这涉及几种分子途径，包括Wnt信号抑制和细胞周期诱导。值得注意的是，在低氧条件下RV转录组的强烈变化对AVP有显著贡献。值得注意的是，上皮间质转化（EMT）的抑制和TP53信号的失调是AVP基因在新生小鼠心脏中的突出标志。此外，TP53相关基因家族的成员在新生小鼠和紫绀TOF心脏的低氧RV中失调。室特异性转录组的综合分析显示，低氧血症特异性变化在RV中比LV更强，导致以前未表征的围产期低氧血症诱导的AVP。值得注意的是，EMT过程的重编程和TP53网络的失调有助于低氧循环过渡期间新生儿心脏的转录组重构。这些见解可能会提高我们对新生儿紫绀型CHD表型低氧血症诱导的发病机制的理解。
Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transitions (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic TOF hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared to LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes.
登录
查看更多内容
DOI：
10.1073/pnas.1808314115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Amelio I;Mancini M;Petrova V;Cairns RA;Vikhreva P;Nicolai S;Marini A;Antonov AA;Le Quesne J;Baena Acevedo JD;Dudek K;Sozzi G;Pastorino U;Knight RA;Mak TW;Melino G
通讯作者：
Melino G
影响因子：
64.8
作者：
Nakada, Yuji;Canseco, Diana C.;Sadek, Hesham A.
通讯作者：
Sadek, Hesham A.
影响因子：
20.1
作者：
von Gise A;Pu WT
通讯作者：
Pu WT
影响因子：
2.7
作者：
von Gise A;Zhou B;Honor LB;Ma Q;Petryk A;Pu WT
通讯作者：
Pu WT
DOI：
10.4161/15384101.2014.949083
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Fischer M;Steiner L;Engeland K
通讯作者：
Engeland K