Epigenetic reactivation of transcriptional programs orchestrating fetal lung development in human pulmonary hypertension

表观遗传学 生物 染色质 染色质免疫沉淀 染色质重塑 基因沉默 转录因子 表型 细胞生物学 增强子 癌症研究 基因 基因表达 遗传学 发起人
作者
Prakash Chelladurai,Carsten Kuenne,Alice Bourgeois,Stefan Günther,Chanil Valasarajan,Anoop V. Cherian,Robbert J. Rottier,Charlotte Romanet,Andreas Weigert,Olivier Boucherat,Christina A. Eichstaedt,Clemens Ruppert,Andreas Güenther,Thomas Braun,Mario Looso,Rajkumar Savai,Werner Seeger,Uta‐Maria Bauer,Sébastien Bonnet,Soni Savai Pullamsetti
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:14 (648) 被引量:30
标识
DOI:10.1126/scitranslmed.abe5407
摘要

Phenotypic alterations in resident vascular cells contribute to the vascular remodeling process in diseases such as pulmonary (arterial) hypertension [P(A)H]. How the molecular interplay between transcriptional coactivators, transcription factors (TFs), and chromatin state alterations facilitate the maintenance of persistently activated cellular phenotypes that consequently aggravate vascular remodeling processes in PAH remains poorly explored. RNA sequencing (RNA-seq) in pulmonary artery fibroblasts (FBs) from adult human PAH and control lungs revealed 2460 differentially transcribed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed extensive differential distribution of transcriptionally accessible chromatin signatures, with 4152 active enhancers altered in PAH-FBs. Integrative analysis of RNA-seq and ChIP-seq data revealed that the transcriptional signatures for lung morphogenesis were epigenetically derepressed in PAH-FBs, including coexpression of T-box TF 4 ( TBX4 ), TBX5 , and SRY-box TF 9 ( SOX9 ), which are involved in the early stages of lung development. These TFs were expressed in mouse fetuses and then repressed postnatally but were maintained in persistent PH of the newborn and reexpressed in adult PAH. Silencing of TBX4 , TBX5 , SOX9 , or E1A-associated protein P300 ( EP300 ) by RNA interference or small-molecule compounds regressed PAH phenotypes and mesenchymal signatures in arterial FBs and smooth muscle cells. Pharmacological inhibition of the P300/CREB-binding protein complex reduced the remodeling of distal pulmonary vessels, improved hemodynamics, and reversed established PAH in three rodent models in vivo, as well as reduced vascular remodeling in precision-cut tissue slices from human PAH lungs ex vivo. Epigenetic reactivation of TFs associated with lung development therefore underlies PAH pathogenesis, offering therapeutic opportunities.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
谢尔顿完成签到,获得积分10
1秒前
奋斗跳跳糖完成签到,获得积分10
2秒前
北极星完成签到 ,获得积分10
4秒前
福娃完成签到,获得积分10
4秒前
yqq完成签到 ,获得积分10
5秒前
6秒前
unborned完成签到 ,获得积分10
7秒前
钱兵完成签到,获得积分10
8秒前
skyinner完成签到 ,获得积分10
10秒前
材料若饥完成签到,获得积分10
11秒前
柳觅夏完成签到,获得积分10
12秒前
cccc完成签到 ,获得积分10
12秒前
阿辉发布了新的文献求助10
12秒前
18秒前
芋圆完成签到 ,获得积分10
20秒前
陈子皮boy发布了新的文献求助10
21秒前
HYCT完成签到 ,获得积分10
24秒前
当女遇到乔完成签到 ,获得积分10
25秒前
caozhi完成签到,获得积分10
28秒前
懒羊羊完成签到 ,获得积分10
28秒前
shrimp5215完成签到,获得积分10
30秒前
昵昵完成签到 ,获得积分10
31秒前
领导范儿应助caozhi采纳,获得10
32秒前
秋婷完成签到 ,获得积分10
37秒前
来到火山口的大企鹅完成签到,获得积分10
37秒前
高高完成签到,获得积分20
38秒前
古今奇观完成签到 ,获得积分10
38秒前
40秒前
啵啵只因完成签到,获得积分10
40秒前
科目三应助啵啵只因采纳,获得10
43秒前
小李完成签到 ,获得积分10
44秒前
ohnono完成签到,获得积分10
49秒前
房东家的猫完成签到,获得积分10
49秒前
东郭雁梅完成签到 ,获得积分10
54秒前
AU完成签到 ,获得积分10
55秒前
ght完成签到 ,获得积分10
57秒前
喜悦的板凳完成签到 ,获得积分10
1分钟前
sdfdzhang完成签到 ,获得积分10
1分钟前
PeterBeau完成签到 ,获得积分10
1分钟前
1分钟前
高分求助中
The late Devonian Standard Conodont Zonation 2000
The Lali Section: An Excellent Reference Section for Upper - Devonian in South China 1500
Nickel superalloy market size, share, growth, trends, and forecast 2023-2030 1000
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 800
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 800
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3244791
求助须知:如何正确求助?哪些是违规求助? 2888434
关于积分的说明 8252939
捐赠科研通 2556941
什么是DOI,文献DOI怎么找? 1385522
科研通“疑难数据库(出版商)”最低求助积分说明 650176
邀请新用户注册赠送积分活动 626303