KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints

  title={KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints},
  author={David N. Ciccone and Hui Su and Sarah Hevi and Frédérique Gay and Hong Lei and Jeffrey Bajko and Guoliang Xu and En Li and Taiping Chen},
Differential DNA methylation of the paternal and maternal alleles regulates the parental origin-specific expression of imprinted genes in mammals. The methylation imprints are established in male and female germ cells during gametogenesis, and the de novo DNA methyltransferase DNMT3A and its cofactor DNMT3L are required in this process. However, the mechanisms underlying locus- and parental-specific targeting of the de novo DNA methylation machinery in germline imprinting are poorly understood… 

DNA methyltransferase 1 (Dnmt1) mutation affects Snrpn imprinting in the mouse male germ line.

The methylation profiles of imprinted regions in the spermatozoa of mice that were heterozygous for a Dnmt1 loss-of-function mutation are analyzed, suggestive of a role of DNMT1 in imprint resetting or maintenance in the male germ line.

Altered expression of BRG1 and histone demethylases, and aberrant H3K4 methylation in less developmentally competent embryos at the time of embryonic genome activation

It is suggested that altered epigenetic modifications of H3K4 around the EGA period may affect the developmental capacity of porcine embryos to reach the blastocyst stage.

Maternal H3K27me3-dependent autosomal and X chromosome imprinting

The role of oocyte-derived histone H3 lysine 27 trimethylation in establishing autosomal imprinting and imprinted XCI is reviewed and this novel maternal H3K27me3-mediated non-canonical imprinting mechanism further emphasizes the important role of parental chromatin in development and could provide the basis for improving the efficiency of embryo cloning.

The Role of Genomic Imprints in Placental Biology

This thesis unambiguously shows that genomic imprints are essential for placental development and engineered a novel targeted deletion of the imprinted Klf14 gene and found it has an effect on placental growth.

Histone demethylase AMX-1 is necessary for proper sensitivity to interstrand crosslink DNA damage

Investigation of the histone demethylase LSD2 homolog AMX-1 in C. elegans uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair and suggested that AMx-1 functions in ICL repair in the germline.

Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

Genetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications are identified, for the first time, and support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent.



The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation

It is suggested that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.

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

DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2, and substitution of key residues in the binding site eliminated the H3 tail–DN MT3L interaction.

Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice.

It is demonstrated that Dnmt3L, a protein sharing homology with DNA methyltransferases, but lacking enzymatic activity, is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes.

Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development.

It is demonstrated, by using conditional knockout mice, that the other known DNA methyltransferases Dnmt3a and DnMT3b are dispensable for the maintenance of the methylation marks at most imprinted loci and that zygotic DNmt1 is expressed in the preimplantation embryo.

Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation

A basis for the recognition and methylation of differentially methylated regions in imprinted genes is suggested, involving the detection of both nucleosome modification and CpG spacing.

Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase

The isolation of KRYPTONITE, a methyltransferase gene specific to H3 Lys 9, identified in a mutant screen for suppressors of gene silencing at the Arabidopsis thaliana SUPERMAN (SUP) locus is reported, which suggests that CpNpG DNA methylation is controlled by histone H 3 Lys 9 methylation, through interaction of CMT3 with methylated chromatin.

Dnmt3L and the Establishment of Maternal Genomic Imprints

Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated, and the defect was specific to imprinted regions, and global genome methylation levels were not affected.

A histone H3 methyltransferase controls DNA methylation in Neurospora crassa

It is demonstrated that recombinant DIM-5 protein specifically methylates histone H3 and that replacement of lysine 9 in hist one H3 with either a leucine or an arginine phenocopies the dim-5 mutation, concluding that DNA methylation depends on histone methylation.