Heritability of gene regulation between organismal generations: molecular mechanisms and developmental functions of intergenerational epigenetic inheritance

In mammalian somatic and germline cells, genomes are extensively DNA methylated (DNAme).  Regulatory CpG-island (CGI) sequences, however, are generally devoid of repressive DNAme. The mechanisms restricting de novo DNAme acquisition at CGIs in germ cells, and the relevance thereof for regulating gene expression and development of offspring have thus far been unknown. We recently identified that the histone H3 lysine 36 dimethyl demethylases KDM2A and KDM2B impede global de novo DNAme (including CGI gene promoters) in oocytes that is catalyzed by the DNMT3A enzyme. We demonstrated that aberrant DNAme established in Kdm2a/Kdm2b double knock-out (dko) oocytes represses transcription from maternal loci in two-cell embryos. Vitally, the lethality of Kdm2a/Kdm2b maternal dko pre-implantation embryos is suppressed by Dnmt3a deficiency during oogenesis arguing that aberrant maternal DNAme impairs embryonic development. In the seminar, I will discuss these and other findings and place them in a broader context of chromatin-based mechanisms of intergenerational epigenetic inheritance.