H4K20 monomethylation inhibition causes loss of genomic integrity in mouse preimplantation embryos

Abstract

Maintaining genomic integrity in mammalian early embryos, which are deficient in DNA damage repair, is critical for normal preimplantation and subsequent development. Abnormalities in DNA damage repair in preimplantation embryos can cause not only developmental arrest, but also diseases such as congenital disorders and cancers. Histone H4 lysine 20 monomethylation (H4K20me1) is involved in DNA damage repair and regulation of gene expression. However, little is known about the role of H4K20me1 during mouse preimplantation development. In this study, we revealed that H4K20me1 mediated by SETD8 is involved in maintaining genomic integrity. H4K20me1 was present throughout preimplantation development. In addition, reduction in the level of H4K20me1 by inhibition of SETD8 activity or a dominant-negative mutant of histone H4 resulted in developmental arrest at the S/G2 phase and excessive accumulation of DNA double-strand breaks. Together, our results suggest that H4K20me1, a type of epigenetic modification, is associated with the maintenance of genomic integrity and is essential for preimplantation development. A better understanding of the mechanisms involved in maintaining genome integrity during preimplantation development could contribute to advances in reproductive medicine and technology.

H4K20me1 and H3K27me3 are concurrently loaded onto the inactive X chromosome but dispensable for inducing gene silencing

“…However, the biological function of these enzymes remains unknown. The study of H4K20me1 during XCI has been hampered by the fact that SETD8 is absolutely required for the progression through mitosis and embryos lacking it die before the onset of XCI (Oda et al, 2009;Shikata et al, 2020).…”

Chromatin landscape dynamics in development of the plant parasitic nematode Meloidogyne incognita

“…during mouse preimplantation development, with this modification playing a key role in the maintenance of genome integrity [40]. M. incognita seems to have the same histone modification machinery as model organisms, and we can, therefore, predict analogous functions for H4K20me1 in cell cycle regulation and the maintenance of genome integrity in this nematode.…”

Chromatin Landscape Dynamics in Development of the Plant Parasitic Nematode Meloidogyne Incognita

“…H4K20me1 levels have been shown to change dynamically during the cell cycle, peaking during the G2/M phase [39]. At the whole-organism scale, dynamic changes in H4K20 methylation have been observed during mouse preimplantation development, with this modi cation playing a key role in the maintenance of genome integrity [40]. M. incognita seems to have the same histone modi cation machinery as model organisms, and we can, therefore, predict analogous functions for H4K20me1 in cell cycle regulation and the maintenance of genome integrity in this nematode.…”