Faculty Opinions recommendation of DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.
Year: 2007
Type: peer-review
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 DNMT3B1,2.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.Null alleles of Dnmt3L are lethal when transmitted through the maternal germ line as a result of a failure to establish maternal genomic imprints during oogenesis, and mutant males show reactivation of retrotransposons and extreme meiotic defects in spermatocytes.The loss of DNA methylation in DNMT3L-deficient male germ cells also causes hyperacetylation of histones and a loss of methylation from lysine 9 of histone H3 (ref. 3). DNMT3L stimulates de novo methylation by DNMT3A2 (refs 4,5) but does not enhance the binding of DNMT3A2Correspondence and requests for materials should be addressed to T.H.B.
Author: Yi Eve Sun
Institution: University of California, Los Angeles
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W4205537037