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

Abstract

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. Here we show that amine oxidase (flavin-containing) domain 1 (AOF1), a protein related to the lysine demethylase KDM1 (also known as LSD1), functions as a histone H3 lysine 4 (H3K4) demethylase and is required for de novo DNA methylation of some imprinted genes in oocytes. AOF1, now renamed lysine demethylase 1B (KDM1B) following a new nomenclature, is highly expressed in growing oocytes where genomic imprints are established. Targeted disruption of the gene encoding KDM1B had no effect on mouse development and oogenesis. However, oocytes from KDM1B-deficient females showed a substantial increase in H3K4 methylation and failed to set up the DNA methylation marks at four out of seven imprinted genes examined. Embryos derived from these oocytes showed biallelic expression or biallelic suppression of the affected genes and died before mid-gestation. Our results suggest that demethylation of H3K4 is critical for establishing the DNA methylation imprints during oogenesis.

Genomic imprinting as an adaptative model of developmental plasticity

“…1, [3]). The role of histone modifications in imprinting control is less clear, however DMRs are characterised by the asymmetrical accumulation of different histone modifications on the two parental chromosomes and recently a requirement for histone demethylation in order to establish germline CpG methylation has been identified at some ICRs [4].…”

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

“…28 However, these features can be found elsewhere in the genome and are not specific to ICRs. By contrast, Kdm1b acts only on a subset of ICRs (for example, ICRs at Mest, Grb10, Plagl1 and Impact loci), 29 although demethylation of H3K4 by this enzyme is consistent with the preference of Dnmt3L for unmethylated H3K4. The involvement of Zfp57 appears to be more restricted, and so far the Snrpn ICR is its only known target in oocytes, although it is involved in imprint maintenance at multiple ICRs after fertilization (see later).…”

“…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.…”

Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase

“…A fundamental question concerns how a specific sequence is selectively methylated by the de novo enzymes in cells. Evidence for cross-talk between DNA methylation and histone modification has been found in various contexts of transcriptional regulation and chromatin functions [4][5][6][7][8]. In the filamentous fungus Neurospora crassa, either the replacement of histone H3 lysine 9 (H3K9) with other amino acids or deletion of the sole H3K9 methyltransferase DIM5 results in the loss of DNA methylation [9].…”