Probing chromatin landscape reveals roles of endocardial TBX20 in septation

Cornelis J. Boogerd, Ivy Aneas, Noboru Sakabe, Ralph J. Dirschinger, Quen J. Cheng, Bin Zhou, Ju Chen, Marcelo A. Nobrega, Sylvia M. Evans

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3023-3035
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number8
DOIs
StatePublished - Aug 1 2016

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Versicans
Chromatin
Gene Regulatory Networks
Transposases
Congenital Heart Defects
Reporter Genes
Cell Movement
Extracellular Matrix
Transcription Factors
Binding Sites
Gene Expression
Mutation
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Boogerd, C. J., Aneas, I., Sakabe, N., Dirschinger, R. J., Cheng, Q. J., Zhou, B., ... Evans, S. M. (2016). Probing chromatin landscape reveals roles of endocardial TBX20 in septation. Journal of Clinical Investigation, 126(8), 3023-3035. https://doi.org/10.1172/JCI85350

Probing chromatin landscape reveals roles of endocardial TBX20 in septation. / Boogerd, Cornelis J.; Aneas, Ivy; Sakabe, Noboru; Dirschinger, Ralph J.; Cheng, Quen J.; Zhou, Bin; Chen, Ju; Nobrega, Marcelo A.; Evans, Sylvia M.

In: Journal of Clinical Investigation, Vol. 126, No. 8, 01.08.2016, p. 3023-3035.

Research output: Contribution to journalArticle

Boogerd, CJ, Aneas, I, Sakabe, N, Dirschinger, RJ, Cheng, QJ, Zhou, B, Chen, J, Nobrega, MA & Evans, SM 2016, 'Probing chromatin landscape reveals roles of endocardial TBX20 in septation', Journal of Clinical Investigation, vol. 126, no. 8, pp. 3023-3035. https://doi.org/10.1172/JCI85350
Boogerd, Cornelis J. ; Aneas, Ivy ; Sakabe, Noboru ; Dirschinger, Ralph J. ; Cheng, Quen J. ; Zhou, Bin ; Chen, Ju ; Nobrega, Marcelo A. ; Evans, Sylvia M. / Probing chromatin landscape reveals roles of endocardial TBX20 in septation. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 8. pp. 3023-3035.
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