Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities

Abstract

Cognitive abilities decline in normal aging, yet the underlying molecular mechanisms are poorly understood. We found that aging was associated with a decrease in the expression of the DNA methyltransferase Dnmt3a2 in the hippocampus and that rescuing Dnmt3a2 levels restored cognitive functions. Moreover, we found that Dnmt3a2 is an activity-regulated immediate early gene that is partly dependent on nuclear calcium signaling and that hippocampal Dnmt3a2 levels determine cognitive abilities in both young adult and aged mice.

The de novo DNA methyltransferase DNMT3A in development and cancer

“…82 In contrast, Oliveira et al reported recently that Dnmt3a2, the shorter isoform encoded by the Dnmt3a gene, controlled cognitive abilities in mice. 26 This effect of Dnmt3a2 might not have been investigated in previous studies. 82 Using gain-and loss-offunction strategies, they found that overexpression of Dnmt3a2 in the hippocampal brain area of elderly mice restored their cognitive skills in long-term-memory test.…”

“…Reducing Dnmt3a2 expression in the hippocampus caused poor performance in young adult mice in long-term-memory test when compared with controls of the same age. 26 These findings suggested that the special isoform Dnmt3a2 played a predominant role in the age-related decline of cognition.…”

“…10 However, several inactivating mutations of DNMT3A in myeloid malignancies [11][12][13][14][15][16][17][18][19][20][21][22][23] and loss of DNMT3A activity at advanced tumor stages 24 were recently identified. In addition, novel roles of DNMT3A in the hematopoiesis system 25 and in the age-related decline of cognition 26 have been revealed. These new data suggested that the role of DNMT3A in mammalian development may be more complex than was previously believed, and indicated that in addition to acting as an oncogene in some circumstances, DNMT3A may also behave as a tumor suppressor in other circumstances.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Whether age‐related changes in DNA methylation are associated with AD pathology is still unclear. An early study showed that overexpression of Dnmt3a2 isoform could improve the cognitive abilities of aged mice (Oliveira, Hemstedt, & Bading, 2012), which points to the importance of DNA methylation in cognitive function.…”

Biological Effects of Polyamines on the Prevention of Aging-associated Diseases and on Lifespan Extension

“…However, aging-associated increases in the methylation of some genes are also reported (Issa et al, 1994;Issa et al, 1996;Wallace et al, 2010). Generally, ODC (Minois et al, 2011) and Dnmt (Lopatina et al, 2002;Oliveira et al, 2012;Romanenko et al, 1998) et al, 2004;Li et al, 2010;Morgan et al, 2005). Because there is a close relationship between Dnmt activities and the methylation status of LFA-1 promoter regions, and since aging is associated with decreased Dnmt activities as well as increased demethylation of the LFA-1 promoter region (Zhang et al, 2002), the agingassociated enhancement of LFA-1 expression seems to be due to the age-dependent decreases in Dnmt activities.…”