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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 mammals1,2. 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 process3,4,5. 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)6, 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 nomenclature7, 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.

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Figure 1: KDM1B is an H3K4 demethylase.
Figure 2: KDM1B deficiency results in H3K4me2 elevation in oocytes and maternal-effect embryonic lethality.
Figure 3: KDM1B-deficient oocytes fail to establish DNA methylation imprints at multiple loci.
Figure 4: Aof1 mat -/+ embryos show loss of monoallelic expression of the affected imprinted genes.

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Acknowledgements

We thank Y. Shi, J. Wang, G. A. Baltus, T. B. Nicholson, S. Kadam and H. M. Chan for discussions, and J. Wang, J. Kurash and G. A. Baltus for technical assistance.

Author Contributions T.C. planned and supervised the project. D.N.C. and T.C. designed the experiments and wrote the manuscript. D.N.C., E.L. and T.C. analysed the data. D.N.C., H.S., S.H., F.G., H.L., J.B. and T.C. carried out the experiments. G.X. generated the DNMT3A and DNMT3L antibodies.

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Correspondence to Taiping Chen.

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All authors except G.X. are employees of Novartis Institutes for Biomedical Research.

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Ciccone, D., Su, H., Hevi, S. et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461, 415–418 (2009). https://doi.org/10.1038/nature08315

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