miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice

Mandelbaum, Amitai D.; Kredo‐Russo, Sharon; Aronowitz, Danielle; Myers, Nadav; Yanowski, Eran; Klochendler, Agnes; Swisa, Avital; Dor, Yuval; Hornstein, Eran

doi:10.1007/s00125-019-4916-z

Cited by 14 publications

(11 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are in agreement with the reported positive impact of miR-17 in the expansion of the β-cell mass occurring during the neonatal period (124). Recently, Mandelbaum et al confirmed these data in vivo using a conditional mouse model in which the miR-17-92/miR-106b-25 cluster was deleted (202). These mice displayed a reduced β-cell mass and up to 50% reduction in total pancreatic insulin content.…”

Section: Mir-17-92/mir-106b-25 Clustersupporting

confidence: 87%

Roles of Noncoding RNAs in Islet Biology

Guay

Jacovetti

Bayazit

et al. 2020

Comprehensive Physiology

View full text Add to dashboard Cite

The discovery that most mammalian genome sequences are transcribed to RNA has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs, including microRNAs, Piwi-associated RNAs, small nucleolar RNAs, tRNAderived fragments, long non-coding RNAs and circular RNAs. While the involvement of microRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of non-coding RNAs are also participating in different aspects of islet physiology. The aim of this review will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the last 15 years on the role of non-coding RNAs in the control of α-and β-cell development and function and to highlight the recent discoveries in the field. We will not only describe the role of non-coding RNAs in the control of insulin and glucagon secretion but will also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their non-coding RNAs inside small extracellular vesicles allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell-to-cell communication between β-cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed.-Circulating non-coding RNAs represent promising biomarkers.

show abstract

Section: Mir-17-92/mir-106b-25 Clustersupporting

confidence: 87%

Roles of Noncoding RNAs in Islet Biology

Guay

Jacovetti

Bayazit

et al. 2020

Comprehensive Physiology

View full text Add to dashboard Cite

show abstract

“…Moreover, we showed in our prior work that mis-expression of either SIX2 or SIX3 was sufficient to suppress proliferation of the human β-cell line EndoCβH1 (Arda et al 2016). Enforcement of the post-mitotic state in β-cells has been linked to attainment of mature function (Helman et al 2016; Puri et al 2018; Mandelbaum et al 2019).…”

Section: Discussionmentioning

confidence: 99%

SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells

Bevacqua

Lam

Peiris

et al. 2020

Preprint

View full text Add to dashboard Cite

The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β-cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human β-cells remain unknown. Here, we show that shRNA-mediated SIX2 or SIX3 suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that SIX2 and SIX3 regulate distinct targets. Loss of SIX2 markedly impaired expression of genes governing β-cell insulin processing and output, glucose sensing, and electrophysiology, while SIX3 loss led to inappropriate expression of genes normally expressed in fetal β-cells, adult a-cells and other non-β-cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, β-cells from diabetic humans with impaired insulin secretion also had reduced SIX2 transcript levels. Revealing how SIX2 and SIX3 govern functional maturation and maintain developmental fate in native human β-cells should advance β-cell replacement and other therapeutic strategies for diabetes.

show abstract

“…In contrast, miRs regulating mature β-cell function should be enriched in NT-3 cells, while those associated with malignancy or response to drug treatment should predominate in BON and QGP cells. To this end, all three cell lines, to a various extent, express the six members of the miR-17-92 cluster (17, 18a, 19a, 19b-1, 20a, 92a), a highly-conserved gene cluster with various roles in β-cell function and differentiation [20][21][22][23][24]. Yet other miRs involved in β-cell/islet cell development and insulin secretion (7-3, 15a, 33a, 182, and 375 [25][26][27][28][29][30]) are more prominent in NT-3 than in BON and QGP cells.…”

Section: Identification Of Mirs Expressed In Bon and Qgp Cellsmentioning

confidence: 99%

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Luley

Biedermann

Künstner

et al. 2020

Cancers

View full text Add to dashboard Cite

Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17-92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial-mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro.Cancers 2020, 12, 691 2 of 18 Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the "islet/insulinoma tumors" (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as "metastasis-like/primary" (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

show abstract

miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice

Cited by 14 publications

References 58 publications

Roles of Noncoding RNAs in Islet Biology

Roles of Noncoding RNAs in Islet Biology

SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Contact Info

Product

Resources

About