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      Impact of Pdx1-associated chromatin modifiers on islet β-cells

      1 , 1 , 1

      Diabetes, Obesity and Metabolism

      Wiley

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          Abstract

          <p class="first" id="P1">Diabetes mellitus arises from insufficient insulin secretion from pancreatic islet β-cells. In type 2 diabetes (T2D), β-cell dysfunction is associated with inactivation and/or loss of transcription factor activity, including Pdx1. Notably, this particular transcription factor is viewed as a master regulator of pancreas development and islet β-cell formation, identity and function. Transcription factors, like Pdx1, recruit coregulators to transduce activating and/or repressing signals to the general transcriptional machinery for controlling gene expression, including modifiers of DNA, histones, and nucleosome architecture. These coregulators impart a secondary layer of control that can be exploited to modulate transcription factor activity. In this review, we describe Pdx1-recruited coregulators that impact chromatin structure, consequently influencing normal β-cell function and likely Pdx1 activity in pathophysiological settings. </p>

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          Most cited references 40

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          Stability and flexibility of epigenetic gene regulation in mammalian development.

           Wolf Reik (2007)
          During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences--transposons, imprinted genes and pluripotency-associated genes--in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.
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            Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.

            Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Histone acetyltransferases.

              Transcriptional regulation in eukaryotes occurs within a chromatin setting and is strongly influenced by nucleosomal barriers imposed by histone proteins. Among the well-known covalent modifications of histones, the reversible acetylation of internal lysine residues in histone amino-terminal domains has long been positively linked to transcriptional activation. Recent biochemical and genetic studies have identified several large, multisubunit enzyme complexes responsible for bringing about the targeted acetylation of histones and other factors. This review discusses our current understanding of histone acetyltransferases (HATs) or acetyltransferases (ATs): their discovery, substrate specificity, catalytic mechanism, regulation, and functional links to transcription, as well as to other chromatin-modifying activities. Recent studies underscore unexpected connections to both cellular regulatory processes underlying normal development and differentiation, as well as abnormal processes that lead to oncogenesis. Although the functions of HATs and the mechanisms by which they are regulated are only beginning to be understood, these fundamental processes are likely to have far-reaching implications for human biology and disease.
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                Author and article information

                Journal
                Diabetes, Obesity and Metabolism
                Diabetes Obes Metab
                Wiley
                14628902
                September 2016
                September 2016
                September 12 2016
                : 18
                : 123-127
                Affiliations
                [1 ]Department of Molecular Physiology and Biophysics; Vanderbilt University; Nashville Tennessee
                Article
                10.1111/dom.12730
                5918695
                27615141
                © 2016
                Product
                Self URI (article page): http://doi.wiley.com/10.1111/dom.12730

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