SUV4-20 activity in the preimplantation mouse embryo controls timely replication

Abstract

Extensive chromatin remodeling after fertilization is thought to take place to allow a new developmental program to start. This includes dynamic changes in histone methylation and, in particular, the remodeling of constitutive heterochromatic marks such as histone H4 Lys20 trimethylation (H4K20me3). While the essential function of H4K20me1 in preimplantation mouse embryos is well established, the role of the additional H4K20 methylation states through the action of the SUV4-20 methyltransferases has not been addressed. Here we show that Suv4-20h1/h2 are mostly absent in mouse embryos before implantation, underscoring a rapid decrease of H4K20me3 from the two-cell stage onward. We addressed the functional significance of this remodeling by introducing Suv4-20h1 and Suv4-20h2 in early embryos. Ectopic expression of Suv4-20h2 leads to sustained levels of H4K20me3, developmental arrest, and defects in S-phase progression. The developmental phenotype can be partially overcome through inhibition of the ATR pathway, suggesting that the main function for the remodeling of H4K20me3 after fertilization is to allow the timely and coordinated progression of replication. This is in contrast to the replication program in somatic cells, where H4K20me3 has been shown to promote replication origin licensing, and anticipates a different regulation of replication during this early developmental time window.

Histone H4K20 tri‐methylation at late‐firing origins ensures timely heterochromatin replication

“…Despite many attempts and similarly to other laboratories (Eid et al, 2016), we were unable to identify a specific H4K20me2 antibody for ChIP experiments, which has precluded exploring further the impact of this Suv4-20h-mediated H4K20me state in our studies. Although we cannot rule out a role of H4K20me2 in DNA replication, our results suggest that this function would be restrained to late-replicating heterochromatin regions.…”

Three-dimensional analysis of nuclear heterochromatin distribution during early development in the rabbit

“…As in mouse, this histone mark was found only on the female pronucleus at the 1-cell stage. However, this mark was quite dispersed in the rabbit female pronucleus, while in the mouse, H4K20me3 signal was found only around NPBs (Probst and Almouzni 2008 ; Eid et al 2016 ). After the 1-cell stage, comparison with the mouse is more complicated.…”

Chromatin plasticity: A versatile landscape that underlies cell fate and identity

“…The heterochromatin mark trimethylated histone 4 Lys 20 (H4K20me3) is undetectable in mouse preimplantation embryos, and ectopic establishment of this mark by expression of Suv4-20h1/h2 hinders development (Fig. 2), likely by altering S-phase progression in this developmental context (32). How these modifications interconnect with H3K27me3 will be important to consider.…”