MafB maintains β-cell identity under MafA-deficient condition
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PROVIDER: PRJNA824305 | ENA |
REPOSITORIES: ENA
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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, and several β-cell-disallowed genes; and 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. Furtherly, the appearance of ALDH1A3+ cell and disappearance of UCN3+ cell also verify the β-cell de-differentiation state. Together, 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.
2022-06-24 | GSE200355 | GEO
Project description:MafA and MafB transcription factors have been shown to be key regulators of insulin and glucagon transcription. MafB is essential for alpha and beta cell differentiation, as MafB deficient mice produced fewer insulin+ and glucagon+ cells during development, with MafA expressed in remaining insulin+ cells. In contrast, beta cell development was reported to be normal in a total MafA knock out, although the animals developed beta cell dysfunction and diabetes as adults. However, we have found that MafB expression is elevated during development and retained in adult insulin+ cells after conditional removal of MafA in the pancreas. These studies will evaluate the broader significance of these insulin and glucagon regulators in alpha and beta cell development and function. Our efforts will focus on determining if the concerted actions of MafA and MafB factors are significant to beta cell formation, and we specifically plan to: Determine how alpha and beta cell differentiation is affected in MafA/MafB compound mutant mice during pancreas development. cDNA microarray studies (pancchip 6.0) with wild type, MafAKO, MafB-/-, and MafAKOMafB-/- mutant E18.5 pancreata will be performed to comprehensively identify genes controlled by MafA and MafB in developing alpha and beta cells.
2014-11-04 | E-MTAB-3070 | biostudies-arrayexpress
Project description:Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (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)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human b cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive 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 novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively, by repressing expression of Gast/GAST and other non-b cell hormones.
2023-05-01 | GSE230728 | GEO
Project description: Not available
| S-EPMC6692125 | biostudies-literature
Project description:Pancreatic Beta-cells are essential for regulating blood glucose levels. Much of our knowledge relating to human Beta-cell development and function has depended on rodent models, which have provided a blueprint to confirm important cellular features in humans. The advent of next generation sequencing studies, however, has highlighted discrepancies in Beta-cells which exist between mice and men. The precise contribution of such differences has not yet been fully appreciated. Numerous studies have identified MAFB to be present in human Beta-cells postnatally, while its expression is restricted to embryonic and neo-natal Beta-cells in mice. Conversely, the related transcription factor MAFA is only active in mature murine Beta-cells and notably, knockout of MAFB has minimal effect on murine Beta-cell development and function, in contrast to MAFA. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to Beta-cell development and function specifically in humans. MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor somatostatin- and pancreatic polypeptide–positive cells at the expense of insulin- and glucagon-producing cells during endocrine cell specification. Our results uncover a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification. Taken together, the current study demonstrates that MAFB has synonymous functions in mice and human Alfa and Beta-cell specification and uncovers previously unappreciated roles in other pancreatic endocrine cell types, in particular Gamma-cells. We propose that under-appreciated differences in rodent versus human pancreatic islet biology may be alleviated by expanding genetic observations in animal models by utilizing hPSCs to better model human Beta-cell development and associated disease pathophysiology such as diabetes.
2020-03-23 | GSE145347 | GEO
Project description:To investigate the function of MAFB in the regulation of human beta cell identity and maturity, we established EndoCbH2 cell lines in which MAFB has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from bulkRNA-seq of 3 biological replicates.
2023-09-21 | GSE228992 | GEO
Project description: Not available
| S-EPMC3189696 | biostudies-literature
Project description:Transformation of Chicken Embryo fibroblast by MafA is dependent on its phosphorylation status. Using microarray analysis, we identify a gene expression subprogram regulated by MafA phosphorylation. Keywords: phosphorylation mediated transcriptional regulation
2007-12-25 | GSE9045 | GEO
Project description:The intent of this experiment was to determine MAFB binding sites in human pancreatic beta cells. This is particularly relevant as MAFB is not expressed in mature rodent beta cells; thus, it may perform unique functions in human. Sequencing was performed following IP with an anti-MAFB antibody using chromatin isolated from the human pancreatic beta cell line, EndoCBH2 cells. Cells were proliferating and untreated when collected.
2020-03-17 | E-MTAB-8612 | biostudies-arrayexpress