Heterochromatin establishment during early mammalian development is regulated by pericentromeric RNA and characterized by non-repressive H3K9me3

Abstract

Upon fertilization in mammals the gametes are reprogrammed to create a totipotent zygote, a process that involves de novo establishment of chromatin domains. A major feature occurring during preimplantation development is the dramatic remodeling of constitutive heterochromatin, although the functional relevance of this is unknown. Here we show that heterochromatin establishment relies on the stepwise expression and regulated activity of Suv39h enzymes. Enforcing precocious acquisition of constitutive heterochromatin results in compromised development and epigenetic reprogramming, demonstrating that heterochromatin remodeling is essential for natural reprogramming at fertilization. We find that de novo H3K9 trimethylation in the paternal pronucleus after fertilization is catalyzed by Suv39h2 and that pericentromeric RNAs inhibit Suv39h2 activity and reduce H3K9me3. De novo H3K9me3 is initially non-repressive for gene expression but instead can bookmark promoters for compaction. Overall, we uncover the functional importance for the restricted transmission of constitutive heterochromatin during reprogramming and a non-repressive role for H3K9me3.

Rebooting the Epigenomes during Mammalian Early Embryogenesis

“…Expression of exogenous gene does not require enhancers in 1-cell mouse embryos but does so at the 2-cell stage when ZGA occurs, supporting permissive chromatin in 1-cell embryos but more repressed chromatin at the 2-cell stage ( Schultz, 2002 ). In line with the notion that heterochromatin is extensively remodeled after fertilization, many repressive epigenetic marks, including DNA methylation, H3K27me3, and H3K9me3, are either missing or in the “immature state” in pre-implantation embryos ( Burton et al., 2020 ; Lee et al., 2014 ; Liu et al., 2016b ; Smith and Meissner, 2013 ; Wang et al., 2018 ; Xia et al., 2019 ; Zheng et al., 2016 ). For example, SUV39H1 is not expressed in 1-cell mouse embryos, coinciding with the absence of constitutive heterochromatin including chromocenters ( Burton et al., 2020 ).…”

“…In mouse, unlike H3K4me3 and H3K27me3, H3K9me3 appears to undergo global resetting on both alleles after fertilization ( Wang et al., 2018 ). The de novo H3K9me3 deposited in 1-cell embryos shows distinct distributions between the two parental alleles, with the paternal, but not the maternal, H3K9me3 being deposited by SUV39H2 ( Burton et al., 2020 ; Wang et al., 2018 ). The allele asymmetry lasts as late as the blastocyst stage ( Wang et al., 2018 ).…”

“…However, such de novo H3K9me3 is non-repressive but instead bookmarks promoters for future compaction. Forced expression of SUV39H1 induced chromocenter formation at the 2-cell stage and compromised pre-implantation development, suggesting that the precocious restoration of constitutive heterochromatin is detrimental to embryo development ( Burton et al., 2020 ). Besides, by using DamID, LADs are shown to be de novo established after fertilization but exhibit atypical genome distribution on the maternal allele in zygotes and on both alleles at the 2-cell stage ( Borsos et al., 2019 ).…”

Centromeric Transcription: A Conserved Swiss-Army Knife

“…In fission yeast, the importance of pericentromeric transcription for heterochromatin formation has been extensively studied (reviewed here [ 86 ]). Beyond fission yeast, only a few studies have addressed directly whether centromeric transcription plays an important role in pericentromeric heterochromatin formation [ 23 , 43 , 141 ]. Why are CENP-A nucleosomes deposited where they are and not somewhere else on the chromosome?…”

Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance

“…Considering the profound influence of heterochromatin on genome stability and cell fate transitions, much effort has been devoted to understanding how heterochromatin domains are established during development and maintained through cell divisions 9,14 . One of the most persistent challenges to heterochromatin maintenance is the response to DNA damage, which can arise at any time, anywhere in the genome 15,16 and poses a major threat to epigenome stability 17,18 .…”