Abhishek Sampath Kumar1, Michelle K. Y. Seah1,*, Ka Yi Ling1,*, Yaju Wang1, Joel H. L. Tan1,2, Sandra Nitsch1, Shu Ly Lim1, Chanchao Lorthongpanich3, Heike Wollmann4, Diana H. P. Low5, Ernesto Guccione2,5, Daniel M. Messerschmidt1,2,#
1 Developmental Epigenetics and Disease Group, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 138673, Singapore
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore
3 Siriraj Center of Excellence for Stem Cell Research, Mahidol University, Bangkok, Thailand
4 NGS Unit of DNA Sequencing Facility, IMCB, A*STAR, 138673, Singapore
Published online ahead of print in Genes & Development on 23 January 2017.
Please see http://genesdev.cshlp.org/content/early/2017/01/23/gad.291195.116.full.pdf+html
Global DNA demethylation is a hallmark of embryonic epigenetic reprogramming. Yet, embryos engage non-canonical DNA methylation maintenance mechanisms to ensure inheritance of exceptional epigenetic germline features to the soma. Besides the paradigmatic genomic imprints these exceptions remain ill-defined and the mechanisms ensuring demethylation resistance in the light of global reprogramming remain poorly understood. Here we show that the Y-linked gene Rbmy1a1 is highly methylated in mature sperm and resists DNA demethylation post-fertilization. Aberrant hypomethylation of the Rbmy1a1 promoter results in its ectopicactivation causing male-specific periimplantation lethality. Rbmy1a1 is a novel target of the TRIM28 complex, which is required to protect its repressive epigenetic state during embryonic epigenetic reprogramming.
Absence of maternal Trim28 results in the ectopic activation of the Y-chromosomal gene RBMY1A1 (red), which is not found in control male embryos (middle row) or mutant females (distinguished by X-linked GFP expression, bottom row). Ectopic activation of RBMY1A1 results in peri-implantation lethality, which is apparent in the morphological abnormality of mutant male embryos at E4.5 (top row).
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