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The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment.

ABSTRACT: Chromatin adapts a distinct structure and epigenetic state in embryonic stem cells (ESCs), but how chromatin is three-dimensionally organized within the ESC nucleus is poorly understood. Because nuclear location can influence gene expression, we examined the nuclear distributions of chromatin with key epigenetic marks in ESC nuclei. We focused on chromatin at the nuclear periphery, a compartment that represses some but not all associated genes and accumulates facultative heterochromatin in differentiated cells. Using a quantitative, cytological approach, we measured the nuclear distributions of genes in undifferentiated mouse ESCs according to epigenetic state and transcriptional activity. We found that trimethyl histone H3 lysine 27 (H3K27-Me(3)), which marks repressed gene promoters, is enriched at the ESC nuclear periphery. In addition, this compartment contains 10-15% of chromatin with active epigenetic marks and hundreds of transcription sites. Surprisingly, comparisons with differentiated cell types revealed similar nuclear distributions of active chromatin. By contrast, H3K27-Me(3) was less concentrated at the nuclear peripheries of differentiated cells. These findings demonstrate that the nuclear periphery is an epigenetically dynamic compartment that might be distinctly marked in pluripotent ESCs. In addition, our data indicate that the nuclear peripheries of multiple cell types can contain a significant fraction of both active and repressed genes.

SUBMITTER: Luo L

PROVIDER: S-EPMC2758804 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment.

Luo Li L Gassman Katherine L KL Petell Lydia M LM Wilson Christian L CL Bewersdorf Joerg J Shopland Lindsay S LS

Journal of cell science 20090922 Pt 20

Chromatin adapts a distinct structure and epigenetic state in embryonic stem cells (ESCs), but how chromatin is three-dimensionally organized within the ESC nucleus is poorly understood. Because nuclear location can influence gene expression, we examined the nuclear distributions of chromatin with key epigenetic marks in ESC nuclei. We focused on chromatin at the nuclear periphery, a compartment that represses some but not all associated genes and accumulates facultative heterochromatin in diffe ...[more]

PMID: 19773359

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Project description:The currently used anti-cancer therapies work by killing cancer cells but result in adverse effects and resistance to treatment, which accelerates aging and causes damage to normal somatic cells. On one hand, chicken and zebrafish embryos can reprogram cancer cells towards a non-tumorigenic phenotype; however, they cannot be used in the clinical practice. On the other hand, embryonic stem cells (ESCs) mimic the early embryonic microenvironment and are easily available. We investigated the therapeutic efficacy of the ESC microenvironment (ESCMe) in human uveal melanoma in vitro and in vivo. Methods: Human uveal melanoma C918 cells co-cultured with ESCs were used to measure the levels of mRNA and protein of the phosphoinositide 3-kinase (PI3K) pathway. Cell proliferation, invasiveness, and tumorigenicity of C918 cells were also analyzed. To mimic the tumor microenvironment in vivo, we co-cultured C918 cells and normal somatic cells with ESCs in a co-culture system and evaluated the therapeutic potential of ESCMe in both cell types. For an in vivo study, a mouse tumor model was used to test the safety and efficacy of the transplanted ESC. Elimination of the transplanted ESCs in mice was carried out by using the ESC-transfected with a thymidine kinase suicidal gene followed by administration of ganciclovir to prevent the formation of teratomas by ESCs. Results: In vitro studies confirmed that ESCMe inhibits the proliferation, invasiveness, and tumorigenicity of C918 cells, and the PI3K agonist abolished these effects. ESCMe suppressed the various malignant behaviors of uveal melanoma cells but enhanced the proliferation of normal somatic cells both in vitro and in vivo. Further, we demonstrated that ESCMe suppressed the PI3K pathway in tumor cells but activated in somatic cells. Conclusions: The ESCMe can effectively suppress the malignant phenotype of uveal melanoma cells and modulate the tumor-promoting aging environment by preventing the senescence of normal cells through the bidirectional regulation of the PI3K signaling. Our results suggest that ESC transplantation can serve as an effective and safe approach for treating cancer without killing cells.

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The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment.

Publications

The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment.

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