Probing chromatin landscape reveals roles of endocardial TBX20 in septation

被引:26
作者
Boogerd, Cornelis J. [1 ]
Aneas, Ivy [2 ]
Sakabe, Noboru [2 ]
Dirschinger, Ralph J. [3 ]
Cheng, Quen J. [3 ]
Zhou, Bin [4 ,5 ,6 ]
Chen, Ju [3 ]
Nobrega, Marcelo A. [2 ]
Evans, Sylvia M. [1 ,3 ,7 ]
机构
[1] UCSD, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA
[2] Univ Chicago, Dept Human Genet, 920 E 58th St CLSC 319, Chicago, IL 60637 USA
[3] UCSD, Dept Med, La Jolla, CA USA
[4] Yeshiva Univ, Albert Einstein Coll Med, Dept Genet, New York, NY 10033 USA
[5] Yeshiva Univ, Albert Einstein Coll Med, Dept Med, New York, NY 10033 USA
[6] Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat, New York, NY 10033 USA
[7] UCSD, Dept Pharmacol, La Jolla, CA USA
关键词
GENE-EXPRESSION; HEART DEVELOPMENT; CARDIAC CHAMBER; ETS FAMILY; DEFECTS; GATA4; VERSICAN; DIFFERENTIATION; IDENTIFICATION; ORGANIZATION;
D O I
10.1172/JCI85350
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Mutations in the T-box transcription factor TBX20 are associated with multiple forms of congenital heart defects, including cardiac septal abnormalities, but our understanding of the contributions of endocardial TBX20 to heart development remains incomplete. Here, we investigated how TBX20 interacts with endocardial gene networks to drive the mesenchymal and myocardial movements that are essential for outflow tract and atrioventricular septation. Selective ablation of Tbx20 in murine endocardial lineages reduced the expression of extracellular matrix and cell migration genes that are critical for septation. Using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we identified accessible chromatin within endocardial lineages and intersected these data with TBX20 ChIP-seq and chromatin loop maps to determine that TBX20 binds a conserved long-range enhancer to regulate versican (Vcan) expression. We also observed reduced Vcan expression in Tbx20-deficient mice, supporting a direct role for TBX20 in Vcan regulation. Further, we show that the Vcan enhancer drove reporter gene expression in endocardial lineages in a TBX20-binding site-dependent manner. This work illuminates gene networks that interact with TBX20 to orchestrate cardiac septation and provides insight into the chromatin landscape of endocardial lineages during septation.
引用
收藏
页码:3023 / 3035
页数:13
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