SETDB1-Mediated Cell Fate Transition between 2C-Like and Pluripotent States

Wu, Kaixin; Li, He; Wang, Yaofeng; He, Jiangping; Shou, Xu; Chen, Yaping; Kuang, Jinqiang; Liu, Jiadong; Guo, Lin; Li, Dongwei; Shi, Ruona; Shen, Li; Wang, Yangming; Zhang, Xiaofei; Wang, Jie; Pei, Duanqing; Chen, Jiekai

doi:10.1016/j.celrep.2019.12.010

Cited by 72 publications

(65 citation statements)

References 70 publications

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“…6f ). Furthermore, many E2F6-repressed germline genes are overexpressed upon SETDB1 inactivation in ESCs in 2i or serum conditions 48 , 49 (Supplementary Fig. 6a, b ).…”

Section: Resultsmentioning

confidence: 96%

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

et al. 2021

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In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development.

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“…6f ). Furthermore, many E2F6-repressed germline genes are overexpressed upon SETDB1 inactivation in ESCs in 2i or serum conditions 48 , 49 (Supplementary Fig. 6a, b ).…”

Section: Resultsmentioning

confidence: 96%

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

et al. 2021

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“…Deletion of LSD/KDM1A leads to an increase of H3K4me2/me3 and H3K27ac, and decrease of H3K9me/me2, as well as expanded fate potential in mESCs ( Macfarlan et al., 2011 ). Loss of SETDB1, the methyltransferase of H3K9me3, initiates a 2-cell-like transition program by inducing the expression of DUX in mESCs ( Wu et al., 2020 ). Conversely, the restoration of repressive marks may restrict cell fate among distinct lineages.…”

Section: Main Textmentioning

confidence: 99%

Rebooting the Epigenomes during Mammalian Early Embryogenesis

Xia

Xie

2020

Stem Cell Reports

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Summary Upon fertilization, terminally differentiated gametes are transformed to a totipotent zygote, which gives rise to an embryo. How parental epigenetic memories are inherited and reprogrammed to accommodate parental-to-zygotic transition remains a fundamental question in developmental biology, epigenetics, and stem cell biology. With the rapid advancement of ultra-sensitive or single-cell epigenome analysis methods, unusual principles of epigenetic reprogramming begin to be unveiled. Emerging data reveal that in many species, the parental epigenome undergoes dramatic reprogramming followed by subsequent re-establishment of the embryo epigenome, leading to epigenetic “rebooting.” Here, we discuss recent progress in understanding epigenetic reprogramming and their functions during mammalian early development. We also highlight the conserved and species-specific principles underlying diverse regulation of the epigenome in early embryos during evolution.

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“…Over the last decade, several epigenetic factors activating or inhibiting the 2CLC state have been identified (Iturbide & Torres-Padilla, 2020), including non-coding RNAs (Choi et al, 2017; Percharde et al, 2018; Yang et al, 2020).Several known negative regulators of the 2CLC state were present among the top hits of the DASH screen.For instance, the SUMO E3-ligase PIAS4 ranked #41(Yan et al, 2019); the chromatin-remodeler p400 ranked #52(Rodriguez-Terrones et al, 2018); the histone demethylase LSD1 ranked #111(Macfarlan et al, 2012); the ncPRC1 subunits RING1B and RYBP ranked #100 and #245 respectively (Rodriguez-Terrones et al, 2018). However, many of the previously known 2CLC epigenetic regulators such as histone chaperone CAF-1(Ishiuchi et al, 2015), transcription factor TRIM28 (De Iaco et al, 2017), the H3K9 methyltransferase SETDB1(Wu et al, 2020), and the m6 A binding protein YTHDC1(Liu et al, 2021) were not ranked high in our screen. This could be due to the lethality associated with these KOs, especially considering the timeline of the DASH screen(3 weeks) in comparison to siRNA screens (Rodriguez-Terrones et al, 2018) with short timelines, where these factors were identified.…”

mentioning

confidence: 78%

“…Rodriguez-Terrones et al, 2018); the histone demethylase LSD1 ranked #111(Macfarlan et al, 2012); the ncPRC1 subunits RING1B and RYBP ranked #100 and #245 respectively (Rodriguez-Terrones et al, 2018). However, many of the previously known 2CLC epigenetic regulators such as histone chaperone CAF-1(Ishiuchi et al, 2015), transcription factor TRIM28(De Iaco et al, 2017), the H3K9 methyltransferase SETDB1(Wu et al, 2020), and the m6 A binding protein YTHDC1(Liu et al, 2021) were not ranked high in our screen. This could be due to the lethality associated with these KOs, especially considering the timeline of the DASH screen(3 weeks) in comparison to siRNA screens (Rodriguez-Terrones et al, 2018) with short timelines, where these factors were identified.…”

mentioning

confidence: 80%

A genome-wide knock-out screen for actors of epigenetic silencing reveals new regulators of germline genes and 2-cell like cell state

Gupta

Yakhou

Albert

et al. 2021

Preprint

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Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements, and higher-order chromatin structures. Expectedly, these chromatin marks are indispensable for mammalian development and alterations often lead to diseases such as cancer. Molecularly, epigenetic mechanisms rely on factors to establish patterns, interpret them into a transcriptional output, and maintain them across cell divisions. A global picture of these phenomena has started to emerge over the years, yet many of the molecular actors remain to be discovered. In this context, we have developed a reporter system sensitive to epigenetic perturbations to report on repressive pathways based on Dazl, which is normally repressed in mouse ES cells. We used this system for a genome-wide CRISPR knock-out screen, which yielded expected hits (DNMT1, UHRF1, MGA), as well as novel candidates. We prioritized the candidates by secondary screens, and led further experiments on 6 of them: ZBTB14, KDM5C, SPOP, MCM3AP, BEND3, and KMT2D. Our results show that all 6 candidates regulate the expression of germline genes. In addition, we find that removal of ZBTB14, KDM5C, SPOP and MCM3AP led to similar transcriptional responses, including a reactivation of the 2-cell like cell (2CLC) signature. Therefore, our genetic screen has identified new regulators of key cellular states.

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SETDB1-Mediated Cell Fate Transition between 2C-Like and Pluripotent States

Cited by 72 publications

References 70 publications

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

Rebooting the Epigenomes during Mammalian Early Embryogenesis

A genome-wide knock-out screen for actors of epigenetic silencing reveals new regulators of germline genes and 2-cell like cell state

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