Zebra Fish Dnmt1 and Suv39h1 Regulate Organ-Specific Terminal Differentiation during Development

Abstract

DNA methylation and histone methylation are two key epigenetic modifications that help govern heterochromatin dynamics. The roles for these chromatin-modifying activities in directing tissue-specific development remain largely unknown. To address this issue, we examined the roles of DNA methyltransferase 1 (Dnmt1) and the H3K9 histone methyltransferase Suv39h1 in zebra fish development. Knockdown of Dnmt1 in zebra fish embryos caused defects in terminal differentiation of the intestine, exocrine pancreas, and retina. Interestingly, not all tissues required Dnmt1, as differentiation of the liver and endocrine pancreas appeared normal. Proper differentiation depended on Dnmt1 catalytic activity, as Dnmt1 morphants could be rescued by active zebra fish or human DNMT1 but not by catalytically inactive derivatives. Dnmt1 morphants exhibited dramatic reductions of both genomic cytosine methylation and genome-wide H3K9 trimethyl levels, leading us to investigate the overlap of in vivo functions of Dnmt1 and Suv39h1. Embryos lacking Suv39h1 had organspecific terminal differentiation defects that produced largely phenocopies of Dnmt1 morphants but retained wild-type levels of DNA methylation. Remarkably, suv39h1 overexpression rescued markers of terminal differentiation in Dnmt1 morphants. Our results suggest that Dnmt1 activity helps direct histone methylation by Suv39h1 and that, together, Dnmt1 and Suv39h1 help guide the terminal differentiation of particular tissues.

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

“…TET: Ten-eleven translocation. [8][9][10], and exists predominantly at cytosines within CG dinucleotides. The reason why CG is favored over other nucleotide contexts relates to its palindromic nature.…”

Germ cell-specific DNA methylation and genome diploidization in primitive vertebrates

“…30,31 In Kaiso-depleted frog and zebrafish, the embryos exhibited failure to develop normal dorsal structures, including axial defect and incomplete head formation, 30,31 the features similar to the phenotype associated with Dnmt1 depletion in zebrafish. 37 These observations suggest the possibility that Kaiso is involved in inhibiting the expression of methylated ntl/Xbra during early embryogenesis. In this study we demonstrated that in the gynogenetic haploid, which inherited only the methylated maternal ntl allele, the insufficiency of ntl expression during early embryogenesis and the failure of anterior notochord formation due to the absence of the unmethylated paternal ntl allele were rescued by removing the methyl-CpG dependent transcriptional repressor Kaiso.…”

Epigenetic landscape and miRNA involvement during neural crest development

“…There are three DNMT families in vertebrates: DNMT1, DNMT2, and DNMT3 (Goll and Bestor, 2005). DNMT1 is implicated in maintaining existing methylation patterns as well as on the regulation of histone methylation (Rai et al, 2006). The functional importance of DNMT2 in vertebrates is largely unclear.…”

“…The functional importance of DNMT2 in vertebrates is largely unclear. However, a recent study in zebrafish demonstrated its involvement in cytoplasmic RNA methylation (Rai et al, 2006). On the other hand, both DNMT3A and 3B have been demonstrated to be essential for de novo methylation throughout embryonic cell differentiation (Chen et al, 2003;Goll and Bestor, 2005;Reik, 2007).…”