Epigenetic Regulation of the DLK1-MEG3 MicroRNA Cluster in Human Type 2 Diabetic Islets

Kameswaran, Vasumathi; Bramswig, Nuria C.; McKenna, Lindsay B.; Penn, Melinda; Schug, Jonathan; Hand, Nicholas J.; Chen, Ying; Choi, In-Chan; Vourekas, Anastassios; Won, Kyoung Jae; Liu, Chengyang; Vivek, Kumar; Naji, Ali; Friedman, Joshua R.; Kaestner, Klaus H.

doi:10.1016/j.cmet.2013.11.016

Cited by 302 publications

(320 citation statements)

References 51 publications

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“…Conversely, several microRNA changes revealed by the screening of human islets were not previously highlighted by the systematic analysis of islets isolated from animal models of diabetes. Indeed, the islets of type 2 diabetic donors were found to express higher levels of miR-187, miR-187*, miR-224 and miR-589 and decreased levels of miR-7, miR-369, miR-487a, miR-655 and miR-656 (see Table 3) [13]. Similar changes in the expression of miR-187 and miR-7a were confirmed by independent research groups [25,34].…”

Section: Can Findings Obtained From Animal Models Of Diabetes Be Extrsupporting

confidence: 65%

“…One such example is the decrease in islet miR-184 expression observed in several independent animal studies [20,21,29,30]. Although changes in the level of this particular non-coding RNA were not detected on global profiling of a small number of human samples [13,34], they were readily confirmed by a study that focused specifically on miR-184 in which a large number of islet preparations were compared [20].…”

Section: Can Findings Obtained From Animal Models Of Diabetes Be Extrmentioning

confidence: 55%

“…miR-7, miR-375 and let-7 family members are among the most abundant microRNAs expressed in human and rodent islets, and miR-7, miR-184 and miR-375 are highly enriched in islets compared with other tissues [12][13][14][15]. The specific role of each of these microRNAs in the regulation of beta cell activities has been investigated in different in vivo and in vitro models.…”

Section: Micrornas As Regulators Of Beta Cell Differentiation and Funmentioning

confidence: 99%

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Role of islet microRNAs in diabetes: which model for which question?

Guay

Regazzi

2014

Diabetologia

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MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans.Keywords Animal models of Diabetes . Diabetes . Human islet donors . Insulin . Islets of Langerhans . MicroRNAs . Pancreatic beta cells . Review MicroRNAs as regulators of beta cell differentiation and functionType 2 diabetes is a chronic metabolic disorder characterised by major alterations in gene expression, which affects several organs, including the islets of Langerhans. A growing number of studies demonstrate that these changes are not only caused by deregulation of key transcription factors such as v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MafA) or pancreatic and duodenal homeobox 1 (PDX1) but are also driven by modifications in the level of another group of molecules regulating gene expression, the microRNAs [1][2][3][4]. MicroRNAs are small non-coding RNAs (typically 21-23 nucleotides long) that pair to the 3′ untranslated region of target mRNAs leading to translational repression and/or a decrease in messenger stability [5].The importance of the microRNA regulatory network for proper differentiation and function of beta cells is highlighted by the phenotypic traits of mice lacking Dicer1, an enzyme essential for the generation of most microRNAs [5]. Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas m...

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Section: Can Findings Obtained From Animal Models Of Diabetes Be Extrsupporting

confidence: 65%

Section: Can Findings Obtained From Animal Models Of Diabetes Be Extrmentioning

confidence: 55%

Section: Micrornas As Regulators Of Beta Cell Differentiation and Funmentioning

confidence: 99%

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Role of islet microRNAs in diabetes: which model for which question?

Guay

Regazzi

2014

Diabetologia

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“…While these protocols are currently dependent upon large quantities of source tissue material in cell culture, this limitation excludes the possibility of studying human islets however the development of the stem cell differentiation protocols may make the CLIP protocol viable for human β-cells in the near future. A recent study profiling miRNAs after the immunoprecipitation of Ago proteins revealed stark differences in the small RNA profile suggesting biochemical approaches to profile miRNAs in FACS-sorted human β-cells may provide insight into distinct populations of miRNAs which interact with specific RNA binding proteins [4] [23]. To date, numerous studies have established specific miRNA:target gene interactions implicating the entire range of β-cell physiology and it appears likely that eventually every functional category (i.e.…”

Section: Identification Of Microrna Targets In the β-Cellmentioning

confidence: 99%

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

Poy

2016

Best Practice & Research Clinical Endocrinology & Metab

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Recent protocols have been developed to differentiate human stem cells and fibroblasts into insulin-producing cells capable of releasing the hormone in a glucosestimulated manner. Limitations remain which prevent bringing these protocols to a clinical setting as these models must still undergo complete characterization. Advances in sequencing technologies have driven the identification of several noncoding RNA species including microRNAs (miRNAs). While their diversity and unique expression patterns across different tissues have made deciphering their precise functional role a significant challenge, studies using both cell lines and transgenic mouse models have made substantial progress in understanding their regulatory role on exocytosis and proliferation of the β-cell. These results also indicate miRNAs play an integral role in the fundamental mechanics of how the cell manages the balance between these independent functions. Continued investigation into miRNA function may uncover mechanisms which can be exploited to improve differentiation protocols in producing fully mature β-cells.

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“…The imprinted DLK1-MEG3 gene region is associated with type 2 diabetes (T2DM). Using HITS-CLIP, Vasumathi et al [82] identified disease-relevant targets of miRNAs in the DLK1-MEG3 gene region, implying their roles in T2DM.…”

Section: Decoding Mirna-target Interactionsmentioning

confidence: 99%

CLIP: viewing the RNA world from an RNA-protein interactome perspective

Zhang

Xie²,

Xu³

et al. 2015

Sci. China Life Sci.

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The pervasive transcription of the genome creates many types of non-coding RNAs (ncRNAs). However, we know very little regarding the functions and the regulatory mechanisms of these ncRNAs. Exploring the interactions of RNA and RNA binding proteins (RBPs) is vital because it can allow us to truly understand how these ncRNAs behave in vivo. High-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP or CLIP-seq) and its variants have been successfully used as systemic techniques to study RBP binding sites. In this review, we will explain the major differences between the CLIP techniques, summarize successful applications of these techniques, discuss limitations of CLIP, present some suggested solutions and project their promising future roles in studying the RNA world. CLIP, CLASH, RPBs, ncRNAs, functional RNomics Citation:Zhang

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Epigenetic Regulation of the DLK1-MEG3 MicroRNA Cluster in Human Type 2 Diabetic Islets

Cited by 302 publications

References 51 publications

Role of islet microRNAs in diabetes: which model for which question?

Role of islet microRNAs in diabetes: which model for which question?

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

CLIP: viewing the RNA world from an RNA-protein interactome perspective

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