Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage

By J. A. Wamstad, Jeffrey M. Alexander, Rebecca M. Truty, Avanti Shrikumar, Fugen Li, K. Eilertson, Huiming Ding, J. Wylie, Alexander R. Pico, John A. Capra and 9 more. Cell, 2012

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SUMMARY Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes. Moreover, we discover a novel pre-activation chromatin pattern at the promoters of genes associated with heart development and cardiac function. We further identify stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation. Together, these findings form a basis for understanding developmentally regulated chromatin transitions during lineage commitment and the molecular etiology of congenital heart disease.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f571dfd08fdf8daedc305ca9aa47dfc8318794a5

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Citations in the corpus

lincRNAs: Genomics, Evolution, and Mechanisms (2013, positive): “…human, mouse, and zebrafish suggested that large gene deserts flanking transcription-factor (TF) genes, particularly those with roles in embryonic development, preferentially harbor lincRNAs (Mercer et al., 2008; Guttman et al., 2009; Ulitsky et al., 2011; Pauli et al., 2012; Wamstad et al., 2012).”
Transcriptional enhancers: from properties to genome-wide predictions (2014, methodology): “The prediction of enhancers using histone marks is now widely used, for example, in the annotation of genome-wide functional elements by individual groups and international consortia 12,52,78,81–84 , and it agrees well with enhancer activity assays 51,72,78 .”
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands (2017, positive): “Together these findings suggest that heart development depends on precise control of transcription mediated by changes in chromatin state in response to developmental signals 36–38 .”
Braveheart, a long non-coding RNA required for cardiovascular lineage commitment (2013, methodology): “Isolation and Manipulation of Primary Mouse Neonatal Cardiomyocytes Murine neonatal cardiomyocytes (nCMs) were isolated from C57B6 mice within the first 24 hr after birth.”
Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers (2014, positive): “Despite the narrow distance, a high-resolution ChIP-exo 26 localization of two general transcription factors (GTFs) that bind core promoters (TBP and TFIIB) reveals an independent transcription initiation complex forms in each direction at divergent TSS pairs at promoters and enhancers (Fig.”