The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming

Abstract

Highlights d Zscan4f is a sequence-specific DNA-binding transcription factor d Zscan4f, a representative of ZSCAN proteins, is a functional partner for Tet2 d The ZSCAN4-TET2 complex regulates metabolic rewiring and activates proteasome activity d Recruiting TET may represent a general biochemical mechanism of ZSCAN proteins

Lactate Activates Germline and Cleavage Embryo Genes in Mouse Embryonic Stem Cells

“…In addition, histone hyperacetylation and DNA demethylation were observed during transient Zscan4 expression [49]. Mechanism studies indicated that ZSCAN4 recruited TET2 through its SCAN domain to target locus and promoted DNA demethylation [50] while promoting degradation of UHRF1 and DNMT1 to suppress DNA methylation [51]. In this study, we observed a significant upregulation of the Zscan4 gene family and a global upregulation of ZGA genes upon lactate supplementation, and this may trigger other downstream events.…”

The chromatin remodelling protein LSH/HELLS regulates the amount and distribution of DNA hydroxymethylation in the genome

“…Various TETs interacting partners have been described, shedding some light on how TET proteins could act on 5hmC levels and distribution. Those include partners such as transcriptional factors/nuclear receptors (IDAX/CXXC4 [20], NANOG [21], PPARγ [22], SP1/PU.1 [23], EBF1 [24], PRDM14 [25], GADD45a [26], NF-κB [27] and ZSCAN4 [28], to name a few), chromatinassociated proteins involved in transcriptional activation (OGT and SET1/COMPASS complex [29]) or repression (SIN3A/HDACs, EZH2, NURD [29,30]) and the promyelocytic leukaemia (PML) protein [31]. The depletion of these factors has various effects on TET enzymes functions, ranging from the regulation of their stability to their recruitment at specific loci or the regulation of their enzymatic activity.…”

Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H 2 S production

“…As early as 2010, we have identified the Warburg effect as a classical hallmark of pluripotent reprogramming, and that chemical compounds modulating the Warburg effect plus small molecules targeting epigenetics enabled single factor OCT4-mediated pluripotent reprogramming (Zhu et al, 2010). Later, many studies supported our initial discovery, and further expanded the knowledge about metabolic regulations of pluripotency induction, including the Warburg effect, mitochondrial dynamics, autophagy, and lipid metabolism (Folmes et al, 2012;Zhang et al, 2012;Ma et al, 2015;Wu et al, 2015;Wu et al, 2016;Wang et al, 2017;Ying et al, 2018;Wu et al, 2019;Cheng et al, 2020;Zhu et al, 2020). Even with all these efforts, currently, the upstream signaling pathways regulating metabolism during reprogramming and how metabolic pathways regulate reprogramming remain incompletely understood.…”