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A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator in the regulation of naïve pluripotency and totipotency in humans

ABSTRACT: A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator in the regulation of naïve pluripotency and totipotency in humans

PROVIDER: PRJNA977717 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24767566_1.fastq.gz	Fastqsanger.gz
	SRR24767566_2.fastq.gz	Fastqsanger.gz
	SRR24767567_1.fastq.gz	Fastqsanger.gz
	SRR24767567_2.fastq.gz	Fastqsanger.gz
	SRR24767568_1.fastq.gz	Fastqsanger.gz

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A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator in the regulation of naïve pluripotency and totipotency in humans

Project description:Regulation of totipotency and naïve pluripotency in humans is crucial for early human embryo development. However, the mechanisms of naïve pluripotency and totipotency regulation in humans, especially the signaling pathways that are involved in these processes, remains largely unknown. We performed a CRISPR/Cas9-based kinome knockout screen to analyze the effect of disrupting 763 human kinases in regulating human naïve pluripotency. Further validation using small molecules revealed that inhibition of ErbB family promoted the transition of hEPSCs to human naïve pluripotent stem cells. More importantly, chemical inhibition of ErbB family also promoted induction of totipotent signatures in human pluripotent cells under different culturing conditions.

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A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator of human naive pluripotency and totipotency.

Project description:Regulation of totipotency and naïve pluripotency is crucial for early human embryo development. However, the mechanisms of naïve pluripotency and totipotency regulation in humans, especially the signaling pathways involved in these processes, remain largely unknown. Here, using the conversion of human extended pluripotent stem cells (hEPSCs) to naïve pluripotent stem cells as a model, we performed a CRISPR/Cas9-based kinome knockout screen to analyze the effect of disrupting 763 kinases in regulating human naïve pluripotency. Further validation using small molecules revealed that the inhibition of ErbB family kinases promoted the transition of hEPSCs to human naïve pluripotent stem cells. More importantly, chemical inhibition of the ErbB family also promoted induction of totipotent signatures in human pluripotent cells under different culture conditions. Our findings provide new mechanistic insights into the regulation of naïve pluripotency and totipotency in humans.

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Project description:The effect of CD151 expression onto the kinome of Jurkat T cells was assessed using kinome analysis. CD151 was expressed in Jurkat T cells by retroviral transduction based on a pMSCV vector. Entrez Gene: 977 UniProtKB: P48509 Jurkat T cells were transduced with the MSCV-CD151 vector and successfully transduced cells were selected using puromycin. For the kinome array experiments 3 independent samples of Jurkat cells and three independent samples of J-CD151 cells were collected. To minimize unspecific background signals, lysates from Jurkat and J-CD151 T cells harvested at different growth stages, which were then pooled to provide one sample prior to loading on the Kinexus antibody microarrays.

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Transcriptional heterogeneity and molecular regulation of totipotency-to-pluripotency transitions in Porcine EPSCs

Project description:The molecular characteristics of EPSCs have long been debated. While human EPSCs (hEPSCs) resemble eight-cell and morula-stage embryos, mouse EPSCs (mEPSCs) more closely resemble post-implantation epiblasts. This study explores the developmental potential and molecular characteristics of porcine expanded pluripotent stem cells (pEPSCs), uncovering their unique transcriptional heterogeneity and similarities to both morula and post-implantation epiblast stages. By performing single-cell transcriptomic analysis, three distinct subpopulations (C1, C2, and C3) were identified, corresponding to totipotency, naïve pluripotency, and primed pluripotency. The use of dual fluorescence reporter systems highlighted transitions between these states, resembling embryonic development. Key findings reveal a dynamic balance model of LEUTX and OTX2 in regulating pluripotency transition that OTX2 promotes the shift from totipotency to primed pluripotency by promoting pluripotency and lineage-priming genes, while LEUTX enhances totipotency by activating totipotency genes. LEUTX-overexpressing cells demonstrated enhanced developmental potential and stability in vitro. The study established a conserved framework for understanding state transitions mediated by OTX2 and LEUTX, with implications for regenerative medicine, developmental biology, and highlight the potential of pEPSCs in agricultural and biomedical applications.

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Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN-null, BRAFV600E melanoma to BRAF/MEK inhibition

Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600Ecells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600Ecells. The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

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