The de novo DNA methyltransferase DNMT3A in development and cancer

Abstract

DNA methylation, one of the best-characterized epigenetic modifications, plays essential roles in development, aging and diseases. The de novo DNA methyltransferase DNMT3A is responsible for the establishment of de novo genomic DNA methylation patterns and, as such, involved in normal development as well as in many diseases including cancer. In recent years, our understanding of this important protein has made significant progress, which was facilitated by stunning development in the analysis of the DNA methylome of multiple organs and cell types. In this review, recent developments in the characterization of DNMT3A were discussed with special emphasis on the roles of DNMT3A in development and cancer.

Keywords: DNA methylation; DNMT3A; cancer; development; epigenetics.

Figure 1. The expression pattern of DNMT3A. (A) The expression of Dnmt3a1 and Dnmt3a2 in male germ cell development. Dnmt3a2 expression was highest in type A spermatogonia, decreased sharply in type B spermatogonia and preleptotene spermatocytes, then went up in leptotene/zygotene spermatocytes to the similar level in type A spermatogonia, followed with a drop again in prepubertal pachytene spermatocytes and pachytene spermatocytes. Moreover, Dnmt3a2 was also expressed in round spermatids and residual bodies/elongating spermatids. Whereas, Dnmt3a1 expression was mostly constant, except for a moderate increase in type B spermatogonia, and showed extremely low levels in round spermatids and residual bodies/elongating spermatids. A, type A spermatogonia; B, type B spermatogonia; PL, preleptotene; L/Z, leptotene/zygotene; PP, prepubertal pachytene spermatocytes; P, pachytene spermatocytes; RS, round spermatids; RB, residual bodies/elongating spermatids. (B) The expression of Dnmt3a1 and Dnmt3a2 during mouse ES cells differentiation. Dnmt3a1 and Dnmt3a2 were all upregulated upon differentiation, with the highest level observed in embryoid bodies (EBs) (4–6 d). However, from 6 d onward, Dnmt3a2 expression decreased dramatically, whereas the level of Dnmt3a1 sustained throughout the examined time-course. (C) Dnmt3a1 and Dnmt3a2 expression in mouse tissues (3 wks. old). Br, brain; Li, liver; Mu, muscle; Te, testis; Ht, heart; Sp, spleen; Th, thymus; St, stomach; Si, small intestine; +, express; -, not express.

Figure 2. Structural domains of DNMT3A protein. Both DNMT3A isoforms (DNMT3A1 and DNMT3A2) have N-terminal regulatory region and C-terminal catalytic region. A 223 (human) or 219 (mouse) amino acid N-terminal domain, which was shown to be able to bind to DNA sequence, is present only in DNMT3A1. The N-terminal regulatory region consists of a moderately conserved PWWP domain and a cysteine-rich (Cys-rich) ADD domain. The PWWP domain of DNMT3A is showed to directly interact with the H3K36m3 mark, while the ADD domain associates with transcriptional factors and epigenetic regulators, and interacts specifically with unmethylated H3K4.^, Finally, the MTase domain resides in the C-terminal region. The oligomerization of DNMT3A and DNMT3L at this structurally conserved domain controls the catalytic mechanism of de novo DNA methylation.