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Modulation of HDAC activity directly reprograme embryonic stem cell to trophoblast stem cell [ESC(Day -2) and induced TSC(Day 2) bulk RNA-Seq]

ABSTRACT: Embryonic stem cells (ESCs) can differentiate into all cell types of each of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal cells. However, these latter transitions occur at low frequency due to epigenetic barriers, the nature of which are not fully understood. Here, we show that mouse ESCs treated with sodium butyrate, an HDAC inhibitor, have a greatly increased 2C-like cell population and can transdifferentiate into trophoblast stem cells (TSCs). Interestingly, this ESC to TSC transition is a direct reprogramming event that does not require transition through a 2C-like state. Mechanistically, butyrate inhibits Class I histone deacetylases activities in LSD1-HDAC1/2 corepressor complex, increasing acetylation levels in the regulatory regions of 2C and TSC specific genes. Importantly, butyrate treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and induce decidualization in vivo. These results uncover how epigenetic changes can expand the potency of ESCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE234787 | GEO | 2024/03/18

REPOSITORIES: GEO

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Project description:Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (âtwo-hitâ cells) that resulted in mTOR activation was unclear. We compared TSC skin hamartomas (facial angiofibromas and periungual fibromas) to normal-appearing skin of the same patient, and observed more proliferation and mTOR activation in hamartoma epidermis. âTwo-hitâ cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed using real-time PCR, and increased amounts of epiregulin protein were demonstrated using immunoprecipitation and ELISA. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by âtwo-hitâ cells in the dermis, and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin. Experiment Overall Design: The study is of case/control design with biological replication. Tumor (case) and normal (control) fibroblast cells were isolated from each of four patients (biological replicates).

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Modulation of HDAC activity directly reprograme embryonic stem cell to trophoblast stem cell [ESC(Day -2) and induced TSC(Day 2) bulk RNA-Seq]

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