Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

Abstract

Summary Post-translational modification by SUMO is a key regulator of cell identity. In mouse embryonic fibroblasts (MEFs), SUMO impedes reprogramming to pluripotency, while in embryonic stem cells (ESCs), it represses the emergence of totipotent-like cells, suggesting that SUMO targets distinct substrates to preserve somatic and pluripotent states. Using MS-based proteomics, we show that the composition of endogenous SUMOylomes differs dramatically between MEFs and ESCs. In MEFs, SUMO2/3 targets proteins associated with canonical SUMO functions, such as splicing, and transcriptional regulators driving somatic enhancer selection. In contrast, in ESCs, SUMO2/3 primarily modifies highly interconnected repressive chromatin complexes, thereby preventing chromatin opening and transitioning to totipotent-like states. We also characterize several SUMO-modified pluripotency factors and show that SUMOylation of Dppa2 and Dppa4 impedes the conversion to 2-cell-embryo-like states. Altogether, we propose that rewiring the repertoire of SUMO target networks is a major driver of cell fate decision during embryonic development.

Waves of sumoylation support transcription dynamics during adipocyte differentiation

“…S4E and Table S18). This is consistent with previous reports (Hendriks et al, 2018; Theurillat et al, 2020), although a unique aspect of our study is the specific enrichment of pathways that are critical for adipose tissue development, function, adaptive thermogenesis, and brown cell differentiation (Fig. S4E-G).…”

“…Understanding the exact molecular mechanisms by which sumoylation regulates transcription factors such as Pparγ/RXR will be the scope of our follow-up studies. Based on previous work by ourselves and others, sumoylation may affect chromatin accessibility (repressive versus permissive), DNA binding capacity or stability of chromatin-bound transcriptional complexes (Chymkowitch et al, 2015a; Chymkowitch et al, 2017; Cossec et al, 2018; Psakhye and Jentsch, 2012; Theurillat et al, 2020).…”

“…The SUMO chromatin landscape is substantially remodeled in response to heat shock, inflammation, oncogene-induced senescence, nutrient deprivation and pro-growth signals (Chymkowitch et al, 2015a; Chymkowitch et al, 2017; Decque et al, 2016; Neyret-Kahn et al, 2013; Nguea et al, 2019; Niskanen et al, 2015). Recent studies have revealed that SUMO is also important for cellular identity (Cossec et al, 2018; Theurillat et al, 2020). However, these studies only compared undifferentiated versus terminally differentiated cells, precluding the sumoylation dynamics that may occur throughout the differentiation process.…”

Identification of SUMO targets required to maintain human stem cells in the pluripotent state

“…Thus, while transcriptional repression of the PRAME gene also involves SUMO, it appears to be mediated by a very different mechanism from silencing of HERV genes as TRIM28, SETDB1 and CBX that are associated with HERV silencing, are not present at the PRAME locus. While our data at HERV entities are consistent with a recent SUMO proteomic analysis in mESCs 52 , the tight SUMO mediated regulation of the PRAME locus appears to be specific to hPSCs. Although the PRAME gene is frequently over-expressed in tumours 53, 54 it appears to play a role in the differentiation of hPSCs into mesenchymal stem cells 55 .…”

Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity

“…In mouse, Dppa2/4 predominantly form heterodimers which is likely required for their function as manipulating levels of just one of the two proteins gives largely the same phenotype as mutating both [ 30 , 32 ]. Dppa2/4 are regulated post-translationally by SUMOylation [ 35 , 36 ] which inhibits their function. It remains to be uncovered whether additional post-translational modifications are involved in fine-tuning their activity.…”