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MafB is required for islet beta cell maturation.

ABSTRACT: Pancreatic endocrine cell differentiation depends on transcription factors that also contribute in adult insulin and glucagon gene expression. Islet cell development was examined in mice lacking MafB, a transcription factor expressed in immature alpha (glucagon(+)) and beta (insulin(+)) cells and capable of activating insulin and glucagon expression in vitro. We observed that MafB(-/-) embryos had reduced numbers of insulin(+) and glucagon(+) cells throughout development, whereas the total number of endocrine cells was unchanged. Moreover, production of insulin(+) cells was delayed until embryonic day (E) 13.5 in mutant mice and coincided with the onset of MafA expression, a MafB-related activator of insulin transcription. MafA expression was only detected in the insulin(+) cell population in MafB mutants, whereas many important regulatory proteins continued to be expressed in insulin(-) beta cells. However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these insulin-deficient cells between E15.5 and E18.5. MafB appears to directly regulate transcription of these genes, because binding was observed within endogenous control region sequences. These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells.

SUBMITTER: Artner I

PROVIDER: S-EPMC1803762 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.

Project description:Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.

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Orphan Nuclear Receptor ERRγ is required for pancreatic islet beta-cell maturation

Project description:We characterized the effect of loss of ERRγ expression in mouse pancreatic islets using adenoviral constructs.

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MLL3 and MLL4 Methyltransferases Bind to the MAFA and MAFB Transcription Factors to Regulate Islet β-Cell Function.

Project description:Insulin produced by islet β-cells plays a critical role in glucose homeostasis, with type 1 and type 2 diabetes both resulting from inactivation and/or loss of this cell population. Islet-enriched transcription factors regulate β-cell formation and function, yet little is known about the molecules recruited to mediate control. An unbiased in-cell biochemical and mass spectrometry strategy was used to isolate MafA transcription factor-binding proteins. Among the many coregulators identified were all of the subunits of the mixed-lineage leukemia 3 (Mll3) and 4 (Mll4) complexes, with histone 3 lysine 4 methyltransferases strongly associated with gene activation. MafA was bound to the ∼1.5 MDa Mll3 and Mll4 complexes in size-fractionated β-cell extracts. Likewise, closely related human MAFB, which is important to β-cell formation and coproduced with MAFA in adult human islet β-cells, bound MLL3 and MLL4 complexes. Knockdown of NCOA6, a core subunit of these methyltransferases, reduced expression of a subset of MAFA and MAFB target genes in mouse and human β-cell lines. In contrast, a broader effect on MafA/MafB gene activation was observed in mice lacking NCoA6 in islet β-cells. We propose that MLL3 and MLL4 are broadly required for controlling MAFA and MAFB transactivation during development and postnatally.

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Examining How the MAFB Transcription Factor Affects Islet ?-Cell Function Postnatally.

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Loss of MafA and MafB expression promotes islet inflammation.

Project description:Maf transcription factors are critical regulators of beta-cell function. We have previously shown that reduced MafA expression in human and mouse islets is associated with a pro-inflammatory gene signature. Here, we investigate if the loss of Maf transcription factors induced autoimmune processes in the pancreas. Transcriptomics analysis showed expression of pro-inflammatory as well as immune cell marker genes. However, clusters of CD4+ T and B220+ B cells were associated primarily with adult MafA-/-MafB+/-, but not MafA-/- islets. MafA expression was detected in the thymus, lymph nodes and bone marrow suggesting a novel role of MafA in regulating immune-cell function. Analysis of pancreatic lymph node cells showed activation of CD4+ T cells, but lack of CD8+ T cell activation which also coincided with an enrichment of naïve CD8+ T cells. Further analysis of T cell marker genes revealed a reduction of T cell receptor signaling gene expression in CD8, but not in CD4+ T cells, which was accompanied with a defect in early T cell receptor signaling in mutant CD8+ T cells. These results suggest that loss of MafA impairs both beta- and T cell function affecting the balance of peripheral immune responses against islet autoantigens, resulting in local inflammation in pancreatic islets.

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Beta-cell regeneration from vimentin+/MafB+ cells after STZ-induced extreme beta-cell ablation.

Project description:Loss of functional beta-cells is fundamental in both type 1 and type 2 diabetes. In situ beta-cell regeneration therefore has garnered great interest as an approach to diabetes therapy. Here, after elimination of pre-existing beta cells by a single high-dose of streptozotocin (STZ), we demonstrated that a considerable amount of beta-like-cells was generated within 48 hrs. But the newly formed insulin producing cells failed to respond to glucose challenge at this time and diminished afterwards. Insulin treatment to normalize the glucose level protected the neogenic beta-like cells and the islet function was also gradually matured. Strikingly, intermediate cells lacking epithelial marker E-cadherin but expressing mesenchymal cell-specific marker vimentin appeared within 16 hrs following STZ exposure, which served as the major source of insulin-producing cells observed at 24 hrs. Moreover, these intermediate cells strongly expressed alpha-cell-specific marker MafB. In summary, the data presented here identified a novel intermediate cell type as beta-cell progenitors, showing mesenchymal cell feature as well as alpha-cell marker MafB. Our results might have important implications for efforts to stimulate beta-cell regeneration.

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Islet-specific microRNA changes driven by nutrient shift trigger postnatal beta-cell maturation - intact islet mRNAs

Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=3) or 3-month-old male rat (n=3) were taken. Total RNA was extracted and mRNA profiling via Illumina single-end sequencing of mRNA-seq libraries was performed.

2014-09-06 | E-GEOD-61179 | biostudies-arrayexpress

Islet-specific microRNA changes driven by nutrient shift trigger postnatal beta-cell maturation - intact islet microRNAs

Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during ?-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature ?-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn ?-cells, suggesting that they contribute to the limited proliferative capacity of adult ?-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=5) or 3-month-old male rat (n=6) were taken. Total RNA was extracted and microRNA profiling was performed using the Illumina TruSeq small RNA kit and single-end sequencing.

2014-09-06 | E-GEOD-61180 | biostudies-arrayexpress

Scrt1, a transcriptional regulator of β-cell proliferation identified by differential chromatin accessibility during islet maturation.

Project description:Glucose-induced insulin secretion, a hallmark of mature β-cells, is achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for establishing an appropriate functional β-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in functional maturation of β-cells remain to be elucidated. Here, we addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. We obtained a genome-wide picture of chromatin accessible sites (~ 100,000) among which 20% were differentially accessible during maturation. An enrichment analysis of transcription factor binding sites identified a group of transcription factors that could explain these changes. Among them, Scrt1 was found to act as a transcriptional repressor and to control β-cell proliferation. Interestingly, Scrt1 expression was controlled by the transcriptional repressor RE-1 silencing transcription factor (REST) and was increased in an in vitro reprogramming system of pancreatic exocrine cells to β-like cells. Overall, this study led to the identification of several known and unforeseen key transcriptional events occurring during β-cell maturation. These findings will help defining new strategies to induce the functional maturation of surrogate insulin-producing cells.

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MafB Maintains <i>β</i>-Cell Identity under MafA-Deficient Conditions.

Project description:The transcription factor MafB plays an essential role in β-cell differentiation during the embryonic stage in rodents. Although MafB disappears from β-cells after birth, it has been reported that MafB can be evoked in β-cells and is involved in insulin+ β-cell number and islet architecture maintenance in adult mice under diabetic conditions. However, the underlying mechanism by which MafB protects β-cells remains unknown. To elucidate this, we performed RNA sequencing using an inducible diabetes model (A0BΔpanc mice) that we previously generated. We found that the deletion of Mafb can induce β-cell dedifferentiation, characterized by the upregulation of dedifferentiation markers, Slc5a10 and Cck, as well as several β-cell-disallowed genes, and by the downregulation of mature β-cell markers, Slc2a2 and Ucn3. However, there is no re-expression of well-known progenitor cell markers, Foxo1 and Neurog3. Further, the appearance of ALDH1A3+ cells and the disappearance of UCN3+ cells also verify the β-cell dedifferentiation state. Collectively, our results suggest that MafB can maintain β-cell identity under certain pathological conditions in adult mice, providing novel insight into the role of MafB in β-cell identity maintenance.

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