We study the gene regulatory events underpinning normal cardiogenesis,
and how these are disrupted in patients with congenital heart disease
and how these are disrupted in patients with congenital heart disease
Ongoing Projects
We are investigating the possibility that congenital heart disease can arise from impairment of chromatin organization dynamics in the developing myocardium
We are investigating the possibility that congenital heart disease can arise from impairment of chromatin organization dynamics in the developing myocardium
Earlier Contributions
We studied the role of chromatin organization dynamics during cardiac differentiation of human embryonic stem cells (hESCs). We found that as hESCs differentiate the heterochromatin compacts and large cardiac genes transition from a repressive (B) to an active (A) compartment. This process correlates with changes in chromatin accessibility and dynamic binding of trans-acting regulators (i.e. CTCF and the congenital heart disease gene GATA4). We also identified a network gene loci that increase their association inter-chromosomally and are targets of the muscle-specific splicing factor RBM20. Genome editing studies demonstrated that TTN pre-mRNA, the main RBM20-regulated transcript in the heart, nucleates RBM20 foci that drive spatial proximity between the TTN locus and other RBM20 targets. This mechanism promotes RBM20-dependent alternative splicing of the resulting transcripts, indicating the existence of a cardiac-specific Trans-Interacting chromatin Domain (TID) functioning as a splicing factory. We hypothesize that TIDs represent a novel type of chromatin organization feature involved in multiple aspects of both DNA and RNA regulation.
We studied the role of chromatin organization dynamics during cardiac differentiation of human embryonic stem cells (hESCs). We found that as hESCs differentiate the heterochromatin compacts and large cardiac genes transition from a repressive (B) to an active (A) compartment. This process correlates with changes in chromatin accessibility and dynamic binding of trans-acting regulators (i.e. CTCF and the congenital heart disease gene GATA4). We also identified a network gene loci that increase their association inter-chromosomally and are targets of the muscle-specific splicing factor RBM20. Genome editing studies demonstrated that TTN pre-mRNA, the main RBM20-regulated transcript in the heart, nucleates RBM20 foci that drive spatial proximity between the TTN locus and other RBM20 targets. This mechanism promotes RBM20-dependent alternative splicing of the resulting transcripts, indicating the existence of a cardiac-specific Trans-Interacting chromatin Domain (TID) functioning as a splicing factory. We hypothesize that TIDs represent a novel type of chromatin organization feature involved in multiple aspects of both DNA and RNA regulation.