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Identification of differential expressed genes between P-RPCs, ESC-RPCs and Dkk1 treated ESC-RPCs through genome-wide transcript profiling

ABSTRACT: Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cells (ESCs). As P-RPCs could successfully integrate into host eyes without development of teratomas or NOG, we sought to identify differentially expressed genes between P-RPCs and ESC-RPCs through genome-wide transcript profiling. Inhibition of Wnt signaling by DKK1 promotes the commitment of ESC-RPCs to more mature retinal cells and reduces the occurrence of NOG to 3%. DKK1-treated ESC-RPCs efficiently integrate to the host retina, form synaptic connections and restore visual function. Here, we report that further differentiation of ESC-derived neural progenitors into retinal progenitor cells (ESC-RPCs) completely eliminates teratomas in ocular transplantation. However, tumor-like neural overgrowth (NOG) occurs in 61% of transplanted eyes.

ORGANISM(S): Mus musculus

PROVIDER: GSE34002 | GEO | 2013/04/16

SECONDARY ACCESSION(S): PRJNA150579

REPOSITORIES: GEO

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Project description:Super Enhancers are a class of DNA Cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis.Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, current research is far from sufficient to reveal the complex mechanisms behind epigenetic modifications.The aim of this study is to explore the function and mechanism of a new Super Enhancer in Pancreatic ductal adenocarcinoma (PDAC) tumors. By using epigenetic modification and chromatin interaction information, we found a new Super Enhancer enriched with abnormal active histone modifications in PDAC tumors and cells, called DKK1-super-enhancer (DKK1-SE).DKK1-SE was grouped according to the activity modification information, and the e1 component was identified as the main active unit by dual luciferase reporter gene system and dCas9-KRAB system.DNA motif analysis and core site deletion assay revealed that the e1 component possessed AP1 transcription factor family binding sites.Mechanically, AP1 activates DKK1 transcriptional activity by recruiting JUND and FOSL2 to induce enhancer chromatin remodeling.CRISPR/ Cas9-mediated deletion of DKK1-SE resulted in significant downregulation of its target gene DKK1.Analysis of TCGA data of PDAC tumors combined with immunohistochemical results of PDAC patients demonstrated that DKK1 was closely related to malignant clinical features of PDAC.Bioinformatics analysis of RNA-seq data showed that DKK1 was mainly related to tumor-related biological functions such as extracellular matrix, cell adhesion, angiogenesis, and cell proliferation.Cell malignant phenotype assay showed that deletion or interference of DKK1-SE significantly inhibited the proliferation, colony formation, migration and invasion of PANC-1, and these phenomena were partially alleviated after restoring DKK1 expression in DKK1-SE deficient cells.Experiments of Subcutaneous transplantation tumor in nude mice and Orthotopic transplantation tumor model showed that DKK1-SE deletion not only inhibited tumor proliferation, but also reduced the complexity of tumor microenvironment, resulting in less angiogenesis of tumor tissues and reduced fibrosis degree.In conclusion, DKK1-SE drives the expression of DKK1 by recruiting AP1 family transcription factors, which plays a carcinogenic role in PDAC tumors and enhances the complexity of the tumor microenvironment.

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Identification of differential expressed genes between P-RPCs, ESC-RPCs and Dkk1 treated ESC-RPCs through genome-wide transcript profiling

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