Table 3.

Roles of HAT, histone methylation, and PARP in cardiovascular development and disease

Class	Chromatin Modifying Factor	Cardiovascular Studies in Animals		Comment	Ref
		Tissue of Gene Modification	Phenotype
HAT	p300	Germline deletion	Lethality at E9.5–E11.5. Thin myocardium and diminished trabeculation.	p300-null embryos have generalized reduction in cell proliferation.	123
		Point mutation that ablates p300 acetyltransferase activity	Lethality at E12.5–E15.5. Thin compact myocardium, ASD*, VSD* reduced coronary vessels.	The acetyltransferase activity of p300 is required for heart development.	124
		Overexpression in myocardium	Cardiac hypertrophy, dilatation and systolic dysfunction.	p300 is a co-activator of the pro-hypertrophic Gata4. It acetylates Gata4 to enhance Gata4’s DNA binding and transcriptional activity.	125, 127
Histone Methylation	JUMONJI	Germline deletion	Variable defects: VSD, non-compaction, double outlets of right ventricle, trabecular hyperplasia.	Jumonji represses cyclin D1 to inhibit myocardial proliferation.	132, 133
	SMYD1	Germline deletion	Malformed right ventricle with little trabeculation.	Smyd1 regulates Hand2, which is essential for right ventricle development.	146, 147
		Knockdown in zebrafish	Disrupted myofibril formation, absent cardiac contraction.	Smyd1 is required for myofibril organization.	148
	WHSC1	Germline deletion	Lethality within 10 days after birth, growth retardation, defective bone formation, ASD, VSD.	Whsc1 associates with Nkx2.5 to repress gene transcription and to regulate cardiac septal formation.	154
PARP	PARP-1 and PARP-2	Germline deletion	Parp-1-null and Parp-2-null mice are viable. Parp-1 and Parp-2 double knockout mice die at E7–E8.	PARP activity is required for Brg1 to repress α-MHC and activate β-MHC in embryonic hearts.	17, 166
			Parp-1-null mutation or inhibition of PARP activity in mice reduces stress-induced cardiac hypertrophy, heart failure, ischemia-reperfusion injury, and infarction.	PARP-1 interacts with HDACs and Brg1 to control cardiac hypertrophy and the pathological MHC switch in hypertrophic hearts. PARP also regulates stress-responsive signaling pathways.	17, 28, 33, 167–174

^*ASD: atrial septal defect. VSD: ventricular septal defect.