PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling

Mzoughi, Slim; Zhang, Jingxian; Héquet, Delphine; Teo, Shun Xie; Fang, Haitong; Xing, Q.; Bezzi, Marco; Seah, Michelle K. Y.; Ong, Sheena L. M.; Shin, Eun Myoung; Wollmann, Heike; Wong, Esther; Al-Haddawi, Muthafar; Stewart, Colin L.; Tergaonkar, Vinay; Loh, Yuin-Han; Dunn, N. Ray; Messerschmidt, Daniel M.; Guccione, Ernesto

doi:10.1038/ng.3922

Cited by 48 publications

(74 citation statements)

References 46 publications

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“…Instead, the expression of IL6R and the co-receptor GP130 and IL6ST was high, suggesting that IL6 but not LIF signaling plays an important role in naïve pluripotency in pig. The pattern is consistent with the previous observations that forced activation of the pathway inhibits the development of mouse embryo to the blastocyst stage 26 and inhibition of the pathway has no obvious effect on the formation of the ICM in pig. 38 In our study, MAPK pathway was found enrichment in ICM of pig, indicating the pathway is essential for advanced progression of porcine ICM.…”

Section: Discussionsupporting

confidence: 92%

“…Instead, GP130 and IL6R were significantly high in ICM. In mouse, the MAPK signaling pathway is important for formation of hypoblast 17,26 and derivation of epiblast stem cells (EpiSCs). The IF analysis of p-STAT3 reinforced the notion that the JAK-STAT signaling pathway was activated in the 2-cell embryo (n = 5) and ICM of EB (n = 3; Figure 5B).…”

Section: Enrichment Of Signaling Pathways In Porcine Pluripotent Cellsmentioning

confidence: 99%

“…However, the activity may be dependent on LIF before the 4-cell stage and IL6 in the later stages. In mouse, the MAPK signaling pathway is important for formation of hypoblast 17,26 and derivation of epiblast stem cells (EpiSCs). 27 However, in consistent with the GO enrichment and KEGG pathways analysis, except RAF1, all the members checked in the pathway were significantly high in ICM ( Figure 5C), indicating MAPK signalling pathway may be important for the further progression of ICM.…”

Section: Enrichment Of Signaling Pathways In Porcine Pluripotent Cellsmentioning

confidence: 99%

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Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Kong

Zhang

et al. 2019

The FASEB Journal

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The inner cell mass (ICM) in blastocyst is the origin of all somatic and germ cells in mammals and pluripotent stem cells (PSCs) in vitro. As the conserved principles between pig and human, here we performed comprehensive single‐cell RNA‐seq for porcine early embryos from oocyte to early blastocyst (EB). We show the specification of the ICM and trophectoderm in morula and the molecular signature of the precursors. We demonstrate the existence of naïve pluripotency signature in morula and ICM of EB, and the specific pluripotent genes and the activity of signalling pathways highlight the characteristics of the naïve pluripotency. We observe the absence of dosage compensation with respect to X‐chromosome (XC) in morula, and incomplete dosage compensation in the EB. However, the dynamics of dosage compensation may be independent of the expression of XIST induced XC inactivation. Our study describes molecular landmarks of embryogenesis in pig that will provide a better strategy for derivation of porcine PSCs and improve research in regenerative medicine.

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Section: Discussionsupporting

confidence: 92%

Section: Enrichment Of Signaling Pathways In Porcine Pluripotent Cellsmentioning

confidence: 99%

Section: Enrichment Of Signaling Pathways In Porcine Pluripotent Cellsmentioning

confidence: 99%

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Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Kong

Zhang

et al. 2019

The FASEB Journal

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“…It has been reported that MAPK signaling plays an important role in CSCs self-renewal and tumorigenicity [15][16][17]. However, how MAPK signaling sustains gastric CSCs self-renewal and tumorigenicity remains largely unknown.…”

Section: Mapk Signaling Regulated the Prr11 Protein Stability Of Gastmentioning

confidence: 99%

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Hu¹,

Song²,

Yao³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. Methods: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. Results: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. Conclusions: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.

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“…The PR domain proteins, many of which have histone methyltransferase activity and others that recruit methyltransferases to DNA, play roles as molecular switches in many developmental processes (Fog et al 2012;Hohenauer and Moore 2012). Little is known about PRDM15, but it functions in pluripotency (Mzoughi et al 2017) and maps to the Down syndrome trisomy region of mouse Chromosome 16 and human Chromosome 21. ZZZ3 is a part of the Ada-Two-A-containing (ATAC) histone acetyltransferase complex, which widely regulates gene expression (Mi et al 2018).…”

Section: Candidate Genes Fall Into Similar Functional Pathwaysmentioning

confidence: 99%

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

Enikanolaiye

Ruston

Zeng

et al. 2019

Preprint

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Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT).We carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU), aiming to identify potential therapeutic entry points. Here we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3,177 Mecp2/Y genomes. Using exome sequencing, genetic crosses and association analysis, we identify 33 candidate genes in 30 of the suppressor lines. A network analysis shows that 61% of the candidate genes cluster into the functional categories of transcriptional repression, chromatin modification or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that are predicted to modulate synaptic signaling or lipid homeostasis. Surprisingly, mutations in genes that function in the DNA damage response (DDR) also improve symptoms in Mecp2/Y mice. The combinatorial effects of multiple loci can be resolved by employing association analysis. One line, which was previously reported to carry a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8 (Rbbp8 or CtIP), which regulates a DDR choice in double stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology directed repair and non-homologous end joining is important for neuronal cells. In this and other lines, the presence of two suppressor mutations confers better symptom improvement than one locus alone, suggesting that combination therapies could be effective in RTT.

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PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling

Cited by 48 publications

References 46 publications

Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

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