DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA

Abstract

Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…Both DNA methylation and histone modifications must cooperate in generating a defined epigenetic environment to respond to toxic stress. A functional connection between histone H3 methylation and DNA methylation state is known to exist, and histone H3K4me3 marks instruct DNA methylation by inhibiting the binding of de novo methylases (131,132). We suggest that both of these mechanisms mediate the transgenerational inheritance and are functionally linked.…”

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

“…1 Our understanding of epigenetic deregulation is advancing as the list of genes and mechanisms mediating the DNA methylation process grows. [39][40][41][42][43] UHRF1 performs a critical function in DNA methylation maintenance 25 ; however, its involvement in TSG promoter hypermethylation in cancer is not yet clear. In the present study, we investigated in NSCLCs the relationship of UHRF1 expression with the hypermethylation status of CDKN2A and RASSF1 promoters, which are among the most frequently hypermethylated genes in this tumor type.…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…Factors and features identified so far as specificity determinants for imprinting in oocytes include: (1) transcription traversing ICRs (Figure 1), 26 (2) unmethylated lysine-4 of histone H3 (H3K4), 27 (3) 10-bp CpG spacing, 28 (4) a histone H3K4 demethylase Kdm1b (Figure 1) 29 and (5) a Krüppel-associated box (KRAB) zinc finger protein Zfp57 (Figure 1). 30 Among these, the first three seem common to all oocyte-methylated ICRs and could be prerequisites for imprint establishment.…”

“…30 Among these, the first three seem common to all oocyte-methylated ICRs and could be prerequisites for imprint establishment. Transcription through ICRs may make the chromatin more accessible by the Dnmt3a-Dnmt3L complex; 26 unmethylated, but not methylated, H3K4 is the high-affinity binding target of Dnmt3L; 27 two CpG sites located 10-bp apart fit very well with the catalytic centers of the heterotetrameric Dnmt3a-Dnmt3L complex. 28 However, these features can be found elsewhere in the genome and are not specific to ICRs.…”