PRC2 specifies ectoderm lineages and maintains pluripotency in primed but not naïve ESCs

Shan, Yongli; Liang, Zechuan; Xing, Qi; Zhang, Tian; Wang, Bo; Tian, Shulan; Huang, Wenhao; Zhang, Yanqi; Yao, Jiao; Zhu, Yanling; Huang, Ke; Liu, Yujian; Wang, Xiaoshan; Chen, Qianyu; Zhang, Jian; Shang, Bizhi; Li, Shengbiao; Shi, Xi; Liao, Baojian; Zhang, Cong; Lai, Keyu; Zhong, Xiaofen; Shu, Xiaodong; Wang, Jinyong; Yao, Hongjie; Chen, Jiekai; Pei, Duanqing; Pan, Guoshun

doi:10.1038/s41467-017-00668-4

Cited by 96 publications

(96 citation statements)

References 65 publications

(96 reference statements)

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“…We obtained that changes in the epigenetic modifications were rather similar in healthy and fetus‐affected AF‐MSCs differentiated toward neural lineage despite differences in the expression of differentiation‐specific genes. Polycomb complexes (PRC1/2) have also been described to be highly involved in neural development by maintaining the repression of inactive genes at different neural differentiation stages (Corley and Kroll, ) and EZH2 is one of the main regulators of human ESCs differentiation into neural ectoderm lineages (Shan et al, ). Our data are in agreement with this because the levels of SUZ12, EZH2 and BMI1 decreased compared to undifferentiated control as neurogenic differentiation proceeded.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic alterations in amniotic fluid mesenchymal stem cells derived from normal and fetus‐affected gestations: A focus on myogenic and neural differentiations

Gasiūnienė

Zentelytė

Treigytė

et al. 2019

Cell Biology International

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Amniotic fluid‐derived mesenchymal stem cells (AF‐MSCs) are autologous to the fetus and represent a potential alternative source for the regenerative medicine and treatment of perinatal disorders. To date, AF‐MSCs differentiation capacity to non‐mesodermal lineages and epigenetic regulation are still poorly characterized. The present study investigated the differentiation potential of AF‐MSCs toward neural‐like cells in comparison to the mesodermal myogenic lineage and assessed epigenetic factors involved in tissue‐specific differentiation. Myogenic and neural differentiation assays were performed by the incubation with specific induction media. Typical MSCs markers were determined by flow cytometry, the expression of lineage‐specific genes, microRNAs and chromatin modifying proteins were examined by RT‐qPCR and Western blot, respectively. AF‐MSCs of normal and fetus‐affected gestations had similar stem cells characteristics and two‐lineage potential, as characterized by cell morphology and the expression of myogenic and neural markers. Two‐lineage differentiation process was associated with the down‐regulation of miR‐17 and miR‐21, the up‐regulation of miR‐34a, miR‐146a and DNMT3a/DNMT3b along with the gradual decrease in the levels of DNMT1, HDAC1, active marks of chromatin (H4hyperAc, H3K9ac, H3K4me3) and the repressive H3K9me3 mark. Differentiation was accompanied by the down‐regulation of PRC1/2 proteins (BMI1/SUZ12, EZH2) and the retention of the repressive H3K27me3 mark. We report that both AF‐MSCs of normal and fetus‐affected gestations possess differentiation capacity toward myogenic and neural lineages through rather similar epigenetic mechanisms that may provide potential applications for further investigation of the molecular basis of prenatal diseases and for the future autologous therapy.

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Section: Discussionmentioning

confidence: 99%

Epigenetic alterations in amniotic fluid mesenchymal stem cells derived from normal and fetus‐affected gestations: A focus on myogenic and neural differentiations

Gasiūnienė

Zentelytė

Treigytė

et al. 2019

Cell Biology International

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“…Given that the suppression of BMP signaling is necessary for neural induction of ectoderm (Wilson and Hemmati-Brivanlou, 1995), its onset may occur before formation of the prospective forebrain. BMP signaling–related targets of PcG proteins identified in embryonic stem cells may be involved in this early process (Shan et al, 2017). The observed increase in Id1 expression in the telencephalon (outside of the dorsal midline) in response to Ring1 deletion from before E10 suggests that BMP signaling remains repressed in this region but becomes derepressed at the dorsal midline, although the mechanisms underlying this difference remain unknown.…”

Section: Discussionmentioning

confidence: 99%

The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

Eto

Kishi

Koseki

et al. 2019

Preprint

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SummaryPatterning of the dorsal-ventral (D-V) axis of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminences. Morphogenetic signaling by bone morphogenetic protein (BMP), Wnt, Sonic hedgehog (Shh), and fibroblast growth factor (FGF) pathways determines regional identity along this axis. It has remained unclear, however, how region-specific expression patterns of these morphogens along the D-V axis are established, especially at the level of epigenetic (chromatin) regulation. Here we show that epigenetic regulation by Ring1, an essential Polycomb group (PcG) protein, plays a key role in formation of ventral identity in the mouse telencephalon. Deletion of the Ring1b or both Ring1a and Ring1b genes in neuroepithelial cells of the mouse embryo attenuated expression of the gene for Shh, a key morphogen for induction of ventral identity, and induced misexpression of dorsal marker genes including those for BMP and Wnt ligands in the ventral telencephalon. PcG protein–mediated trimethylation of histone H3 on lysine-27 (H3K27me3) was also apparent at BMP and Wnt ligand genes in wild-type embryos. Importantly, forced activation of Wnt or BMP signaling repressed the expression of Shh in organotypic and dissociated cultures of the early-stage telencephalon. Our results thus indicate that epigenetic regulation by PcG proteins—and, in particular, that by Ring1— confers a permissive state for the induction of Shh expression through suppression of BMP and Wnt signaling pathways, which in turn allows the development of ventral identity in the telencephalon.

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“…Interestingly, preventing the redistribution of epigenetic marks during the transition to a naïve state is sufficient to block changes in chromatin compaction at several exemplar regions, thereby directly linking epigenome remodelling with aspects of genome organisation (McLaughlin et al). The transcriptome and cell state of mouse and human naïve PSCs are largely unaffected by experimentally disrupting Polycomb levels (Galonska et al, 2015;Moody et al, 2017;Riising et al, 2014;Shan et al, 2017). In contrast, primed PSCs are sensitive to the removal of Polycomb proteins (Collinson et al, 2016;Moody et al, 2017;Shan et al, 2017;Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The transcriptome and cell state of mouse and human naïve PSCs are largely unaffected by experimentally disrupting Polycomb levels (Galonska et al, 2015;Moody et al, 2017;Riising et al, 2014;Shan et al, 2017). In contrast, primed PSCs are sensitive to the removal of Polycomb proteins (Collinson et al, 2016;Moody et al, 2017;Shan et al, 2017;Wang et al, 2018). These observations collectively imply that the stable transition from a naïve to a primed state of pluripotency requires the reconfiguration of DNA interactions to provide a coordinated set of 'poised' regulatory signals to control promoter priming.…”

Section: Discussionmentioning

confidence: 99%

Network analysis of promoter interactions reveals the hierarchical differences in genome organisation between human pluripotent states

Chovanec

Collier

Krueger

et al. 2019

Preprint

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SUMMARYA complex and poorly understood interplay between 3D genome organisation, transcription factors and chromatin state underpins cell identity. To gain a systems-level understanding of this interplay, we generated a high-resolution atlas of annotated chromatin interactions in naïve and primed human pluripotent stem cells and developed a network-graph approach to examine the atlas at multiple spatial scales. Investigating chromatin interactions as a network uncovered highly connected hubs that changed substantially in interaction frequency and in transcriptional co-regulation between pluripotent states.Small hubs frequently merged to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. Importantly, we identified state-specific differences in enhancer activity and interactivity that corresponded with widespread reconfiguration of transcription factor binding and target gene expression. These findings provide multilayered insights into the gene regulatory control of human pluripotency and our systems-based network approach could be applied broadly to uncover new principles of 3D genome organisation. RESULTS Promoter interaction mapping in naïve and primed human PSCsWe used PCHi-C to profile the global, high-resolution interactomes of 22,101 promoters in isogenic human naïve and primed PSCs. There was a strong concordance in pairwise interaction read counts between the biological replicates of the same cell type (r 2 >0.95; Figure S1A); therefore we merged replicates for all downstream analyses. PCHi-C data normalisation and signal detection using the CHiCAGO pipeline (Cairns et al., 2016) identified 75,091 significant cis-interactions between baited promoters and other genomic regions in naïve PSCs, and 83,782 in primed PSCs ( Figure S1B). Just under half of the interactions were common to both cell types (n=39,360). As expected, trans-interactions represented a small minority of promoter interactions (354 interactions). In both cell types, the majority of significant interactions were between the promoters of protein-coding genes and non-promoter genomic regions ( Figure S1B).Processed datasets from this large-scale resource are available through the Open Science Framework (https://osf.io/XXXXX) and Table S1, and raw sequencing reads have been deposited to the Gene Expression Omnibus (accession GSEXXXXXX). Network visualisation of promoter interactomesWe next developed a computational approach called Canvas (Chromosome architecture network visualisation at scales) to visualise high-resolution, capture-based DNA interaction data at a network scale.Network graphs were constructed where each node of the network represents an individual HindIII genomic fragment (average size, 4 kb) and each edge represents a significant interaction between nodes ( Figure 1A). We combined all significant interactions detected in naïve and primed PSCs to produce a single, unified network graph, which retains information about whether an interaction is shared or cell type-specific ( Figu...

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PRC2 specifies ectoderm lineages and maintains pluripotency in primed but not naïve ESCs

Cited by 96 publications

References 65 publications

Epigenetic alterations in amniotic fluid mesenchymal stem cells derived from normal and fetus‐affected gestations: A focus on myogenic and neural differentiations

Epigenetic alterations in amniotic fluid mesenchymal stem cells derived from normal and fetus‐affected gestations: A focus on myogenic and neural differentiations

The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

Network analysis of promoter interactions reveals the hierarchical differences in genome organisation between human pluripotent states

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