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Epigenetic regulation is required to ensure the precise spatial and temporal pattern of gene expression that is necessary for embryonic development. Although the roles of some epigenetic modifications in embryonic development have been investigated in depth, the role of methylation at lysine 79 (H3K79me) is poorly understood. Dot1L, a unique methyltransferase for H3K79, forms complexes with distinct sets of co-factors. To further understand the role of H3K79me in embryogenesis, we generated a mouse knockout of  Mllt10 , the gene encoding Af10, one Dot1L complex co-factor. We find homozygous  Mllt10  knockout mutants ( Mllt10 -KO) exhibit midline facial cleft. The midfacial defects of  Mllt10 -KO embryos correspond to hyperterolism and are associated with reduced proliferation of mesenchyme in developing nasal processes and adjacent tissue. We demonstrate that H3K79me level is significantly decreased in nasal processes of  Mllt10 -KO embryos. Importantly, we find that expression of  AP2α , a gene critical for midfacial development, is directly regulated by Af10-dependent H3K79me, and expression  AP2α  is reduced specifically in nasal processes of  Mllt10 -KO embryos. Suppression of H3K79me completely mimicked the  Mllt10 -KO phenotype. Together these data are the first to demonstrate that Af10-dependent H3K79me is essential for development of nasal processes and adjacent tissues, and consequent midfacial formation.

Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development