Stem Cell Models to Investigate the Role of DNA Methylation Machinery in Development of Neuropsychiatric Disorders

Table 1

Effects of DNMT deficiency and overexpression in development/differentiation.

S. number	Type of the defect	Model system	Phenotype(s)	Reference
1	DNMT1 deficiency	Mouse (knockout)	Lethality at midgestation with imprinting and DNA methylation defects	[10]
		Mouse (conditional knockout in precursor cells in central nervous system)	Degeneration of neurons	[11]
		Mouse embryonic stem cells (ESCs)	Differentiated neurons do not survive, self-renewal is unaffected	[16]
		Hematopoietic stem cells (HSCs)	Poor retention in niches, deficient self-renewal, and defective hematopoiesis	[18]
2	DNMT3a deficiency	Mouse (knockout)	Failure to develop to term	[13]
		Mouse ESCs (knockout)	No effect on self-renewal, progressive loss of DNA methylation, and ability to differentiate	[19]
		Conditional knockout in hematopoietic lineage	Block in differentiation and expanded number of HSCs in bone marrow	[20]
3	DNMT3b deficiency	Mouse (knockout)	Death within four weeks after birth	[13]
		Mouse ESCs (knockout)	Self-renewal unaffected, progressive loss of DNA methylation, and ability to differentiate	[19]
		Conditional knockout in hematopoietic lineage	Defects are milder than in case of DNMT3a deficiency in HSCs; double mutants (deficient in both DNMT3A and DNMT3B) have more severe defects	[20]
4	DNMT3L deficiency	Mouse (knockout)	Females: stochastic imprinting patterns	[14]
			Males: low spermatogonia and wide-spread methylation defects	[15]
5	DNMT1 overexpression	Mouse (transgenic)	Lethality at midgestation due to imprinting defects	[12]
		Mouse ESCs (targeted knocking to increase the levels of DNMT1	Abnormal neuronal differentiation with upregulated NMDA receptor activity	[21]
6	DNMT3a and DNMT1 overexpression	Schizophrenia and bipolar patients with psychosis	Aberrant hypermethylation and downregulation of REELIN and GAD67	[22]