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RNA-Seq of Ctcfl transgenic mouse ES cells

ABSTRACT: Ctcfl, a paralog of Ctcf, also known as BORIS (Brother of Regulator of Imprinted Sites), is a testis expressed gene whose function is largely unknown. As a cancer testis antigen, it is often expressed in tumor cells and also seen in two benign human vascular malformations, juvenile angiofibromas (JA) and infantile hemangiomas (IH). To better understand the function of Ctcfl we created tetracycline-inducible Ctcfl transgenic mice. We show that when Ctcfl expression is induced during embryogenesis, it results in intrauterine growth retardation, developmental eye malformations, multi-organ pathologies, vascular defects, and early neonatal lethality. This phenotype resembles prior mouse models which perturb the TGFB pathway. Embryonic stem cells with the Ctcfl transgene reproduce the same phenotype in ES cell: tetraploid chimeras. RNA-Seq of the Ctcfl ES cells revealed 14 genes, including a number of transcription factors/ co-activators, and signal transduction pathway genes that are significantly deregulated by Ctcfl expression. Bioinformatics analysis revealed the TGFB pathway to be most affected by embryonic Ctcfl expression. We propose that our transgenic mice reiterate a developmental program normally reserved for spermatogenesis that results in multiple organ pathology when expressed in embryogenesis as a result of the TGFB pathway dysregulation. Understanding of the phenotypic consequence of Ctcfl expression in non-testicular cells and elucidating downstream targets of Ctcfl has the potential to explain its role as a cancer testis antigen (CTA) and its involvement in two, if not more, human vascular malformations.

ORGANISM(S): Mus musculus

PROVIDER: GSE72178 | GEO | 2015/08/19

SECONDARY ACCESSION(S): PRJNA293245

REPOSITORIES: GEO

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Project description:A cavernous hemangioma, well-known as vascular malformation, is present at birth, grows proportionately with the child, and does not undergo regression. Although a cavernous hemangioma has well-defined histopathological characteristics, its origin and formation remain unknown. In the present study, we characterized the cellular heterogeneity of cavernous hemangioma using single-cell RNA sequencing (scRNA-seq). The main contribution of the present study is the discovery of mesenchymal stem cells (MSCs) that cause cavernous hemangioma formation and may be abnormally or incompletely differentiated from epiblast stem cells. EGFR inhibitors are the potential drugs to treat cavernous hemangiomas. Other new findings include the responsive ACKR1 positive endothelial cell (ACKR1+EC) and BTNL9 positive endothelial cell (BTNL9+EC) and the BTNL9-caused checkpoint blockade enhanced by the CXCL12-CXCR4 signalling. The activated CD8+T and NK cells may highly express CCL5 for their infiltration in cavernous hemangiomas, independent on the tumor cell-derived CCL5-IFNG-CXCL9 pathway. The plasmacytoid dendritic cells (pDCs) function for anti-tumour as CD8+T cells in cavernous hemangiomas. The oxidised low-density lipoprotein (oxLDL) and scavenger receptors (SRs) may play an important role in the immune responses in the tumour microenvironment of cavernous hemangiomas. Notably, we propose that oxLDL induces the oxLDL-OLR1-NLRP3 pathway in M1-like macrophages via the over-expression of OLR1, whereas oxLDL induces the oxLDL-SRs-C1q pathway in M2-like macrophages via the over-expression of many SRs (LILRB5, etc) except OLR1. The highly expressed EREG in M1-like macrophages and the highly expressed EGFR in MSCs may cause MSC proliferation and the tumour progression. The present study revealed the origin of cavernous hemangiomas and reported the marker genes, cell types and molecular mechanisms, which are associated with the origin, formation, progression, diagnosis or therapy of cavernous hemangiomas. Our discoveries facilitate the development of gold standards for molecular diagnosis and effective drugs for treatment, and enrich the fundamental knowledge in the research field of immune, cancer and even cell biology.

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RNA-Seq of Ctcfl transgenic mouse ES cells

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