A Novel Regulatory Factor Recruits the Nucleosome Remodeling Complex to Wingless Integrated (WNT) Signaling Gene Promoters in Mouse Embryonic Stem cells.
ABSTRACT Nucleosome Remodeling and Deacetylation (NuRD) complex is required for modulating the transcription of essential pluripotency genes in ESC self-renewal. MBD3 is considered a key player in the formation of a functional NuRD complex. The recruitment of MBD3 to methylated promoters may require other prerequisite factors. We show that Cyclin Dependent Kinase 2-Associated Protein 1 (CDK2AP1), an essential gene for early embryonic development, plays a role in pluripotency of ESC by engaging MBD3 to the promoter region of Wnt signalling genes. The occupancy of MBD3 on several promoters of Wnt genes was significantly lost in the absence of CDK2AP1, resulting in hyper-activation of Wnt. We propose that the transcriptional modulation of Wnt pathway mediated by NuRD requires the presence of essential auxiliary components, such as CDK2AP1, that may aid the association of the complex with the specific focal region of the target promoters.
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- "Despite these reported discrepancies between mouse and human somatic cells, it is generally agreed that treatment of somatic cells with HDAC inhibitors during reprogramming can induce changes that drive cells toward the pluripotent state due to increased histone acetylation and activation of gene expression. Two recent studies showed that the nucleosome remodeling and deacetylation (NuRD) complex containing HDAC1 and HDAC2 is functionally associated with suppression of pluripotency-associated gene expression and promotion of lineage commitment in mESCs103,104. These studies reiterate the significant role of HDACs in the regulation of cellular pluripotency and suggest that HDACs regulate pluripotency through a mechanism involving chromatin remodeling. "
ABSTRACT: Post-translational modifications (PTMs) are known to be essential mechanisms used by eukaryotic cells to diversify their protein functions and dynamically coordinate their signaling networks. Defects in PTMs have been linked to numerous developmental disorders and human diseases, highlighting the importance of PTMs in maintaining normal cellular states. Human pluripotent stem cells (hPSCs), including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), are capable of self-renewal and differentiation into a variety of functional somatic cells; these cells hold a great promise for the advancement of biomedical research and clinical therapy. The mechanisms underlying cellular pluripotency in human cells have been extensively explored in the past decade. In addition to the vast amount of knowledge obtained from the genetic and transcriptional research in hPSCs, there is a rapidly growing interest in the stem cell biology field to examine pluripotency at the protein and PTM level. This review addresses recent progress toward understanding the role of PTMs (glycosylation, phosphorylation, acetylation and methylation) in the regulation of cellular pluripotency.Cell Research advance online publication 12 November 2013; doi:10.1038/cr.2013.151.Cell Research 11/2013; 24(2). DOI:10.1038/cr.2013.151 · 11.98 Impact Factor
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ABSTRACT: DNA methylation and chromatin dynamics in embryonic stem cell regulation. OA Stem Cells 2014 May 18;2(1):8. Critical review Competing interests: None declared. Conflict of interests: None declared. All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript. All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure. Abstract Introduction Self-renewal and pluripotency are two most prominent properties of stem cells that are regulated by intrinsic factors that maintain intricate balances among important molecular factors. Many of transcription factors that are involved in the regulation of stemness genes or differentiation-related genes ensure its timely expression for the maintenance or differentiation of stem cells during development. In addition to the genetic factors, the epigenetic regulation has been well recognized as a critical process in the control and maintenance of stem cell properties. This article will highlight recent advances on the epigenetic regulation in stem cells, especially in the context of DNA methylation, chromatin dynamics, and nuclear remodeling histone deacetylase (NuRD) complex in the regulation of stem cell self-renewal and maintenance. Furthermore, we briefly discuss impact of adoption of stem cell technologies in regenerative medicine. Conclusion Studies on epigenetic regulation in stem cells will advance our understanding towards how pluripotent stem cells acquire differentiation competency that leads to the initiation of somatic cell growth control, an important topic that is currently largely unclear. Detailed understanding of molecular regulations during embryonic stem cell differentiation and development will contribute to our understanding on developmental process with utility for regenerative therapeutics.
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ABSTRACT: The nucleosome remodeling and deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity, and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis, and accelerated aging. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer.Translational Research 05/2014; 165(1). DOI:10.1016/j.trsl.2014.05.003 · 4.04 Impact Factor