A model of dynamic stability of H3K9me3 heterochromatin to explain the resistance to reprogramming of differentiated cells

Abstract

Despite their dynamic nature, certain chromatin marks must be maintained over the long term. This is particulary true for histone 3 lysine 9 (H3K9) trimethylation, that is involved in the maintenance of healthy differentiated cellular states by preventing inappropriate gene expression, and has been recently identified as the most efficient barrier to cellular reprogramming in nuclear transfer experiments. We propose that the capacity of the enzymes SUV39H1/2 to rebind to a minor fraction of their products, either directly or via HP1α/β, contributes to the solidity of this mark through (i) a positive feedback involved in its establishment by the mutual enforcement of H3K9me3 and SUV39H1/2 and then (ii) a negative feedback sufficient to strongly stabilize H3K9me3 heterochromatin in post-mitotic cells by generating local enzyme concentrations capable of counteracting transient bursts of demethylation. This model does not require direct molecular interactions with adjacent nucleosomes and is favoured by a series of additional mechanisms including (i) the protection of chromatinbound SUV39H1/2 from the turnovers of soluble proteins, which can explain the uncoupling between the cellular contents in SUV39H1 mRNA and protein; (ii) the cooperative dependence on the local density of the H3K9me3 of HP1α/β-dependent heterochomatin condensation and, dispensably (iii) restricted enzyme exchanges with chromocenters confining the reactive bursts of SUV39H1/2 in heterochromatin. This mechanism illustrates how seemingly static epigenetic states can be firmly maintained by dynamic and reversible modifications.

Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming

“…H3K27 demethylase Utx enhances reprogramming (Mansour et al, 2012), whereas another demethylase, Jmjd3, inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination (Zhao et al, 2013). H3K9 methylation restricts reprogramming events, and its methyltransferases and demethylases dramatically regulate induction of induced pluripotent stem cell (iPSC) formation in both fibroblasts and pre-iPSCs (Chen et al, 2013;Jehanno et al, 2017;Sridharan et al, 2013). The H3K36 demethylases Jhdm1a/1b have been shown to enhance reprogramming in a vitamin C-dependent manner (Liang et al, 2012;Wang et al, 2011).…”

Epigenetic states of donor cells significantly affect the development of somatic cell nuclear transfer (SCNT) embryos in pigs

“…H3K9me3 is an important repressive epigenetic marker whose abundance changes dynamically during mammalian embryonic development (Becker, Nicetto, & Zaret, ; Jehanno, Flouriot, Le Goff, & Michel, ). H3K9me3 negatively affects the development of 2‐cell mouse embryos, whereby reduced H3K9me3 levels at this stage can overcome the embryonic development block in this animal (Liu et al, ).…”

TIP60 recruits SUV39H1 to chromatin to maintain heterochromatin genome stability and resist hydrogen peroxide-induced cytotoxicity

“…A key to the mechanisms of TIP60 function in genome stability might lie in its cooperation with suppressor of variegation 3-9 homolog 1 (SUV39H1), an H3K9 histonelysine methyltransferase (Fritsch et al 2010;Kaniskan et al 2015;Vaquero et al 2007). SUV39H1 is a heterochromatinenriched enzyme that also transiently accumulates around centromeres during mitosis (Chiba et al 2015): it has various well-documented functions, but importantly is critical for maintaining heterochromatin and genome stability (Jehanno et al 2017;Shirai et al 2017;Wang et al 2013). Understanding how SUV39H1 is recruited to chromatin is critical for understanding of heterochromatin structure maintenance and genome stability.…”