Cancer-Related Epigenome Changes Associated with Reprogramming to Induced Pluripotent Stem Cells

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Cancer Research (Impact Factor: 9.33). 10/2010; 70(19):7662-73. DOI: 10.1158/0008-5472.CAN-10-1361
Source: PubMed


The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety.

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Available from: William Matsui, Dec 25, 2013
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    • "The definition of pluripotency relies upon a cell’s ability to differentiate into the three embryonic germ layers, and in the case of stem cells, to self-renew [29]. Tumor formation coincides with both pluripotency and self-renewal and has emerged as a critical factor in determining the pluripotent capacities of both ES and iPS cells [30-33]. However, as seen in ES and iPS cells, the capacity for tripoblastic differentiation and self-renewal is frequently uncontrolled, and often materializes in teratoma formation, hindering the exploitation of their pluripotency for regenerative purposes. "
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    ABSTRACT: In 2010, Multilineage Differentiating Stress Enduring (Muse) cells were introduced to the scientific community, offering potential resolution to the issue of teratoma formation that plagues both embryonic stem (ES) and induced pluripotent (iPS) stem cells. Isolated from human bone marrow, dermal fibroblasts, adipose tissue and commercially available adipose stem cells (ASCs) under severe cellular stress conditions, Muse cells self-renew in a controlled manner and do not form teratomas when injected into immune-deficient mice. Furthermore, Muse cells express classic pluripotency markers and differentiate into cells from the three embryonic germ layers both spontaneously and under media-specific induction. When transplanted in vivo, Muse cells contribute to tissue generation and repair. This review delves into the aspects of Muse cells that set them apart from ES, iPS, and various reported adult pluripotent stem cell lines, with specific emphasis on Muse cells derived from adipose tissue (Muse-AT), and their potential to revolutionize the field of regenerative medicine and stem cell therapy.
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    • "Additional promoter methylation profiles in IMR90 cell lines were obtained from GRO ID: GSM868008[22], GEO ID: GSM739940[23], and GEO ID: GSM375442[24]. They were compared with IMR90 promoter methylation profile, GEO ID: "
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    ABSTRACT: miRNA regulation of target genes and promoter methylation were known as primary epigenetic regula- tion of gene expression. However, how they cooperatively regulate gene expression was not discussed extensively. We found that promoter methylation was miRNA-targeting-specific. In other words, promoter methylation of genes was significantly correlated to miRNAs which target the genes. It was also found that miRNA-targeting-specific pro- moter hypomethylation was related to the miRNA regulation of target genes; the genes with miRNA-targeting-specific promoter hypomethylation were downregulated during cell senescence and upregulated during differentiation.
    Full-text · Technical Report · Dec 2012
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    • "Prior studies suggest that epigenetic reprogramming is involved in the induction of pluripotent stem cells [12]. We therefore investigated promoter methylation patterns in the HMGA1 iPSCs and reprogramming pools using the Illumina Infinium Methylation27 platform, which includes probes for 27,576 loci (Fig. S5). "
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    ABSTRACT: Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear. We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state. Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.
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