Postnatal DNA demethylation and its role in tissue maturation.

Development in mammals is accompanied by specific de novo and demethylation events that are thought to stabilize differentiated cell phenotypes. We demonstrate that a large percentage of the tissue-specific methylation pattern is generated postnatally. Demethylation in the liver is observed in thousands of enhancer-like sequences associated with genes that undergo activation during the first few weeks of life. Using. conditional gene ablation strategy we show that the removal of these methyl groups is stable and necessary for assuring proper hepatocyte gene expression and function through its effect on chromatin accessibility. These postnatal changes in methylation come about through exposure to hormone signaling. These results define the molecular rules of 5-methyl-cytosine regulation as an epigenetic mechanism underlying cellular responses to. changing environment

What is a β cell? - Chapter I in the Human Islet Research Network (HIRN) review series

BACKGROUND: The pancreatic β cell, as the sole source of the vital hormone insulin, has been under intensive study for more than a century. Given the potential of newly created insulin-producing cells as a treatment or even cure of type 1 diabetes (T1D) and possibly in severe cases of type 2 diabetes (T2D), multiple academic and commercial laboratories are working to derive surrogate glucose-responsive, insulin-producing cells. SCOPE OF REVIEW: The recent development of advanced phenotyping technologies, including molecular, epigenomic, histological, or functional, have greatly improved our understanding of the critical properties of human β cells. Using this information, here we summarize the salient features of normal, fully functional adult human β cells, and propose minimal criteria for what should rightfully be termed 'β cells' as opposed to insulin-producing but not fully-functional surrogates that we propose should be referred to as 'β-like' cells or insulin-producing cells. MAJOR CONCLUSIONS: Clear criteria can be established to differentiate fully functional, mature β cells from 'β-like' surrogates. In addition, we outline important knowledge gaps that must be addressed to enable a greater understanding of the β cell

Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity

All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin(+) cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies

Intraislet glucagon signaling is critical for maintaining glucose homeostasis

Glucagon, a hormone released from pancreatic a cells, plays a key role in maintaining proper glucose homeostasis and has been implicated in the pathophysiology of diabetes. In vitro studies suggest that intraislet glucagon can modulate the function of pancreatic ß cells. However, because of the lack of suitable experimental tools, the in vivo physiological role of this intraislet cross-talk has remained elusive. To address this issue, we generated a mouse model that selectively expressed an inhibitory designer GPCR (Gi DREADD) in a cells only. Drug-induced activation of this inhibitory designer receptor almost completely shut o? glucagon secretion in vivo, resulting in markedly impaired insulin secretion, hyperglycemia, and glucose intolerance. Additional studies with mouse and human islets indicated that intraislet glucagon stimulates insulin release primarily by activating β cell GLP-1 receptors. These fndings strongly suggest that intraislet glucagon signaling is essential for maintaining proper glucose homeostasis in vivo. Our work may pave the way toward the development of novel classes of antidiabetic drugs that act by modulating intraislet cross-talk between a and ß cells

The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus

Introduction: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target. Background: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential. Conclusion: Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes

The role of T cell miRNAs for regulatory T cell induction in islet autoimmunity.

BACKGROUND: microRNAs (miRNAs) have emerged as critical contributors to immune regulation and homeostasis, and their dysregulation is involved in the aberrant differentiation and function of T cell subsets. In type 1 diabetes (T1D), the clinically overt disease is preceded by a presymptomatic phase which is marked by the presence of islet autoantibodies while the individual is still normoglycemic. Recent analyses revealed impaired regulatory T (Treg) cell induction from naive CD4+ T cells during this early phase of autoimmunity. SCOPE OF THE REVIEW: In this review article, we aim to discuss important recent insights into miRNA regulation of immune homeostasis and activation. Specifically, we highlight the role of miRNAs as biomarkers in autoimmunity and T1D as well as the contribution of specific miRNAs and their downstream pathways to the onset and progression of islet immunity. Furthermore, we focus on critical next steps required to establish miRNAs as biomarkers to predict disease onset and progression and as novel targets of future prevention and treatment strategies to control autoimmunity. MAJOR CONCLUSIONS: Several recent studies have provided considerable insight into the miRNA regulation of immune homeostasis and how dysregulated miRNAs contribute to onset and progression of islet autoimmunity. Specifically, high levels of individual miRNAs such as miR92a and miR181a are involved in impaired Treg induction during the onset of islet autoimmunity, thereby contributing to disease pathogenesis. The recent advancements in the field suggest miRNAs as potential biomarkers for islet autoimmunity and their direct targeting, especially in a T cell-specific manner, could contribute to the reestablishment of immune homeostasis and ultimately interfere with the onset of islet autoimmunity

Epigenetics and epigenomics: implications for diabetes and obesity

The American Diabetes Association convened a research symposium, "Epigenetics and Epigenomics: Implications for Diabetes and Obesity" on 17-19 November 2017. International experts in genetics, epigenetics, computational biology, and physiology discussed the current state of understanding of the relationships between genetics, epigenetics, and environment in diabetes and examined existing evidence for the role of epigenetic factors in regulating metabolism and the risk of diabetes and its complications. The authors summarize the presentations, which highlight how the complex interactions between genes and environment may in part be mediated through epigenetic changes and how information about nutritional and other environmental stimuli can be transmitted to the next generation. In addition, the authors present expert consensus on knowledge gaps and research recommendations for the field