Erasure of Cellular Memory by Fusion with Pluripotent Cells

Tae, Jeong; Han, Dong Wook; Gentile, Luca; Sobek-Klocke, Ingeborg; Stehling, Martin; Lee, Hoon Taek; Schöler, Hans R.

doi:10.1634/stemcells.2006-0691

Cited by 39 publications

(30 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The fusion hybrid cells carried similar epigenetic characteristics to ES cells (18 -26), which re-exhibited activated histone modifications and a DNA hypomethylation epigenetic state within the Oct4 promoter (24,27). In this research, aberrant epigenetic silencing of p16…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 52%

H3K27 Trimethylation Is an Early Epigenetic Event of p16 Silencing for Regaining Tumorigenesis in Fusion Reprogrammed Hepatoma Cells

Yao

Zhang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Stable epigenetic silencing of p16INK4a is a common event in hepatocellular carcinoma (HCC) cells, which is associated with abnormal cell proliferation and liberation from cell cycle arrest. Understanding the early epigenetic events in silencing p16INK4a expression may illuminate a prognostic strategy to block HCC development. Toward this end, we created a reprogram cell model by the fusion mouse HCC cells with mouse embryonic stem cells, in which the ES-Hepa hybrids forfeited HCC cell characteristics along with reactivation of the silenced p16INK4a . HCC characteristics, in terms of gene expression pattern and tumorigenic potential, was restored upon induced differentiation of these reprogrammed ES-Hepa hybrids. The histone methylation pattern relative to p16INK4a silencing during differentiation of the ES-Hepa hybrids was analyzed. H3K27 trimethylation at the p16 INK4a promoter region, occurring in the early onset of p16 INK4a silencing, was followed by H3K9 dimethylation at later stages. During the induced differentiation of the ES-Hepa hybrids, H3K4 di-and trimethylations were maintained at high levels during the silencing of p16 INK4a , strongly suggesting that H3K4 methylation events did not cause the silencing of p16 INK4a . Our results suggested that the enrichment of H3K27 trimethylation, independent of H3K9 dimethylation, trimethylation, and DNA methylation, was an early event in the silencing of p16INK4a during the tumor development. This unique chromatin pattern may be a heritable marker of epigenetic regulation for p16INK4a silencing during the developmental process of hepatocellular carcinogenesis. Hepatocellular carcinoma (HCC)4 is a worldwide malignancy with a survival rate of Ͻ5% and an average survival of Ͻ1 year after diagnosis (1). Elucidating the molecular mechanisms in HCC development is essential for improving the prognosis efficiency. From Western blotting and immunohistochemical analyses in the HCC cell line and primary HCC samples, poorly differentiated tumors showed loss of p16INK4a to a great extent (2, 3). Aberrant silencing of p16 INK4a , an inhibitor of D-type cyclin-CDK4/CDK6 complexes, could allow mammary epithelial cells to escape senescence during G 1 to S phase, resulting in the triggering of neoplastic process, pre-malignant lesions, and progress in a variety of cancers (4 -9). Unlike the silencing of p16 INK4a in pancreatic adenocarcinoma, glioblastoma, certain leukemias, non-small cell lung cancer, and bladder carcinoma (10, 11), which is caused by mutations and homozygous deletions, the silencing of p16 INK4a in HCC is caused mainly by epigenetic modulations, including DNA hypermethylation, in association with repressive histone modifications, H3K27 trimethylation, and H3K9 di-and trimethylation (2,3,(12)(13)(14). However, the present results reflected the stable epigenetic silencing state in full-fledged cancers or cancer cell lines, the early epigenetic status prior to the transcriptional repression of p16 INK4a in HCC initiation remains largely unknown. This greater u...

show abstract

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 52%

H3K27 Trimethylation Is an Early Epigenetic Event of p16 Silencing for Regaining Tumorigenesis in Fusion Reprogrammed Hepatoma Cells

Yao

Zhang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Consequently, one major limiting step in somatic cell reprogramming, namely activation of the endogenous Oct4 locus (35,36), is overcome almost immediately after exogenous factor expression. In Oct4-GFP reporter MEFs, GFP + cells were detected as early as day 3 to 4 after expressing 6F, which is comparable to somatic cell nuclear transfer (37) or cell fusion (38). Therefore, technically, 6F should facilitate further development of nongenetic modifying reprogramming such as using episome and mRNA (39,40).…”

Section: Discussionmentioning

confidence: 92%

Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1

Wang

Yang

Liu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

224

206

View full text Add to dashboard Cite

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expressing four transcription factors: Oct4, Sox2, Klf4, and c-Myc. Here we report that enhancing RA signaling by expressing RA receptors (RARs) or by RA agonists profoundly promoted reprogramming, but inhibiting it using a RAR-α dominant-negative form completely blocked it. Coexpressing Rarg (RAR-γ) and Lrh-1 (liver receptor homologue 1; Nr5a2) with the four factors greatly accelerated reprogramming so that reprogramming of mouse embryonic fibroblast cells to ground-state iPSCs requires only 4 d induction of these six factors. The six-factor combination readily reprogrammed primary human neonatal and adult fibroblast cells to exogenous factor-independent iPSCs, which resembled ground-state mouse ES cells in growth properties, gene expression, and signaling dependency. Our findings demonstrate that signaling through RARs has critical roles in molecular reprogramming and that the synergistic interaction between Rarg and Lrh1 directs reprogramming toward ground-state pluripotency. The human iPSCs described here should facilitate functional analysis of the human genome.embryonic stem cell | RAREoct | piggyBac transposition | SH-iPSC

show abstract

“…In a previous study, it was found that the somatic cell genome could be reprogrammed by day 2 postfusion, as evidenced by activation of somatic Oct4-GFP transgene expression, which was detected by visualization of the fluorescence signal, around 44 -48 hours after fusion [17]. According to our unpublished data, reprogrammed Oct4-GFP-positive OG2 hybrids exhibited complete demethylation of the Oct4 PE locus by day 2 postfusion, whereas the hybrids exhibited gradual demethylation of the Oct4 PP locus, which was similar to that of the pluripotent fusion partner F9 EC cells by day 9 postfusion (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For the derivation of NSCs, brain tissue was collected from 12.5-to 16.5-days post coitum (dpc) OG2/ROSA26 and GOF18 heterozygous female mice according to a previous protocol [17]. Isolated NSCs were grown in DMEM-Ham's F-12 medium (Gibco-BRL) supplemented with 20 ng/ml epidermal growth factor, 20 ng/ml basic fibroblast growth factor, B27 supplement (Gibco-BRL), 8 mM HEPES, 2 mM glutamine, 100 U/ml penicillin, and 100 mg/ml streptomycin.…”

Section: Cell Culturementioning

confidence: 99%

See 1 more Smart Citation

Pluripotential Reprogramming of the Somatic Genome in Hybrid Cells Occurs with the First Cell Cycle

et al. 2007

Self Cite

View full text Add to dashboard Cite

The fusion of pluripotent embryonic cells with somatic cells results in reprogramming of the somatic cell genome. Oct4-green fluorescent protein (GFP) transgenes that do not contain the proximal enhancer (PE) region are widely used to visualize reprogramming of the somatic to the pluripotent cell state. The temporal onset of Oct4-GFP activation has been found to occur 40 -48 hours postfusion. We asked whether activation of the transgene actually reflects activation of the endogenous Oct4 gene. In the current study, we show that activation of an Oct4-GFP transgene that contains the PE region occurs within 22 hours of fusion. In addition, demethylation of the Oct4-GFP transgene and that of the endogenous Oct4 and Nanog genes was found to occur within 24 hours of fusion. As this timing corresponds with the timing of cell cycle completion in embryonic stem cells and fusion hybrids (ϳ22 hours), we postulate that pluripotential reprogramming of the somatic cell genome begins during the first cell cycle after the fusion of a somatic cell with a pluripotent cell and has been completed by day 2 postfusion. STEM CELLS 2008;26:445-454 Disclosure of potential conflicts of interest is found at the end of this article.

show abstract

Erasure of Cellular Memory by Fusion with Pluripotent Cells

Cited by 39 publications

References 32 publications

H3K27 Trimethylation Is an Early Epigenetic Event of p16 Silencing for Regaining Tumorigenesis in Fusion Reprogrammed Hepatoma Cells

H3K27 Trimethylation Is an Early Epigenetic Event of p16 Silencing for Regaining Tumorigenesis in Fusion Reprogrammed Hepatoma Cells

Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1

Pluripotential Reprogramming of the Somatic Genome in Hybrid Cells Occurs with the First Cell Cycle

Contact Info

Product

Resources

About