scholarly journals Groucho co-repressor proteins regulate β cell development and proliferation by repressing Foxa1 in the developing mouse pancreas

Development ◽  
2021 ◽  
Vol 148 (6) ◽  
Author(s):  
Alexandra Theis ◽  
Ruth A. Singer ◽  
Diana Garofalo ◽  
Alexander Paul ◽  
Anila Narayana ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Cell Development ◽  
Mouse Genetics ◽  
Pancreas Development ◽  
Β Cell ◽  
Repressor Proteins ◽  
Early Lethality

ABSTRACT Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the in vivo role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of Grg3 there is compensatory upregulation of Grg4. Grg3/4 double mutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and Foxa1, a master regulator of the liver program. Neurod1, an essential β cell transcription factor and predicted target of Foxa1, becomes downregulated in Grg3/4 mutants, resulting in reduced β cell proliferation, hyperglycemia, and early lethality. These findings uncover novel functions of GRG-mediated repression during pancreas development.

scholarly journals Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

scholarly journals Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Sha Sumei ◽  
Kong Xiangyun ◽  
Chen Fenrong ◽  
Sun Xueguang ◽  
Hu Sijun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Human Cancer ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Survival Times

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

scholarly journals Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

2012 ◽  
pp. 235-243 ◽  
Author(s):  
Norman Balcazar Morales ◽  
Cecilia Aguilar de Plata
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

scholarly journals The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 638-642 ◽  
Author(s):  
Yasuhiko Kamikubo ◽  
R. Katherine Hyde ◽  
Ling Zhao ◽  
Lemlem Alemu ◽  
Cecilia Rivas ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Myeloid Leukemia ◽  
Single Copy ◽  
Full Length ◽  
Myeloproliferative Disease ◽  
Chromosome 16 ◽  
C Terminus ◽  
Acute Myeloid

Abstract The C-terminus of CBFβ-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-multimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFβ-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFβ-SMMHC (CBFβ-SMMHCΔC95). Embryos with a single copy of CBFβ-SMMHCΔC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBFβ-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFβ-SMMHC. Importantly, unlike mice expressing full-length CBFβ-SMMHC, none of the mice expressing CBFβ-SMMHCΔC95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBFβ-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

scholarly journals Transcription factors that shape the mammalian pancreas

Diabetologia ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 1974-1980
Author(s):  
Rachel E. Jennings ◽  
Raphael Scharfmann ◽  
Willem Staels
Keyword(s):  
Transcription Factors ◽  
Neonatal Diabetes ◽  
Mouse Genetics ◽  
Pancreas Development ◽  
Human Pancreas ◽  
Cellular Models ◽  
Monogenic Forms Of Diabetes ◽  
Exocrine Cell

Abstract Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best ‘model’ for studying human pancreas development are individuals with monogenic forms of diabetes. In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes.

The Proto-Oncogene LRF Is Essential for Normal Mature B Cell Development and Germinal Center Formation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1788-1788
Author(s):  
Nagisa Sakurai ◽  
Manami Maeda ◽  
Sung-UK Lee ◽  
Julie Teruya-Feldstein ◽  
Takahiro Maeda
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Transitional B Cells ◽  
Notch Pathways ◽  
Secondary Lymphoid Organs

Abstract LRF (Leukemia/Lymphoma Related Factor, also known as Pokemon, FBI-1, OCZF and ZBTB7a) was originally identified as an interaction partner of the oncoprotein BCL6. LRF can act as a proto-oncogene by repressing the tumor suppressor ARF and cooperates with BCL6 in MEF (mouse embryonic fibroblasts) immortalization. It is highly expressed in human Non-Hodgkin Lymphoma (NHL) cases, in the pathogenesis of which BCL6 is known to be involved (Maeda et al. Nature 2005). Inducible inactivation of the LRF gene in mouse Hematopoietic Stem Cells (HSCs) results in complete block of early B cell development at the HSC/progenitor stages and concomitant development of double positive (DP) T cells in the bone marrow (BM) (Maeda et al. Science 2007). While these findings clearly illustrate key roles of LRF in normal and malignant B cell development, it is not fully identified as to which B cell stages LRF is required during normal B cell development. To elucidate the role of LRF in B cells in vivo, we established and characterized B cell-specific LRF conditional knockout (KO) mice. We took advantage of mb-1 Cre knock-in mice, in which Cre expression is restricted to the B cells after the ProB cell stage. B cell compartments in the BM (PreProB, ProB, PreB and immatureB) are grossly normal in LRFF/ Fmb1-Cre mice. The LRF gene was efficiently eliminated in BM CD19+ B cells revealed by quantitative real-time PCR assay. Furthermore, LRF protein was not detected in purified CD19+ B cells, but seen in CD19-non-B cells, confirming the specific inactivation of the LRF gene in B cells. Thus, despite its critical role at the HSC/progenitor stages, LRF was found to be dispensable for the survival of normal BM B cells. These findings are consistent with the fact that GSI treatment (Maeda et al. Science 2007) or Notch1 loss (Lee and Maeda, unpublished) rescues the defects in early B cell development seen in LRFF/FMx1-Cre+ mice. Notch signaling is necessary for the transitional B cells to commit to the marginal zone B cells (MZB). Inactivation of the component of the Notch pathways in mice results in no MZB development. On the contrary, deletion of the MINT/SHARP gene, a suppressor of Notch signaling, leads to increase of MZB cells and concomitant reduction of follicular B (FOB) cells, indicating that Notch induces MZB cell fate at the transitional B cell stage. Given that LRF is a potent Notch suppressor at the HSC/progenitor stages, we hypothesized that LRF opposes Notch pathway in mature B cells as well. To test this hypothesis, we characterized mature B cell development in LRFF/Fmb1-Cre mice. While transitional B cells were largely unaffected in LRFF/Fmb1-Cre mice, we observed a slight but statistically significant reduction of follicular (FO) B cells (B220+CD19+AA4.1-CD1d-CD23+) and concomitant increase of MZB cells (B220+CD19+AA4.1-CD1d+CD23-) as seen in MINT/SHARP knockout mice. Thus, LRF may also oppose Notch pathways at the branching point for the FOB vs. MZB fate decision. Finally, to determine the role of LRF in Germinal Center (GC) formation in vivo, we characterized secondary lymphoid organs of LRFF/Fmb1-Cre mice after antigen stimulation. Both spleen and Peyer’s Patches were analyzed two weeks after immunization with Chicken Gamma Globulin (NP-CGG). While a GC reaction was robustly induced in control mice upon immunization, GC formation was significantly impaired in LRFF/Fmb1-Cre mice as revealed by immuno-histochemical analysis (IHC) and FACS. Only few GC cells (B220+CD19+FAS+CD38-PNA+) were observed in spleens, and the absolute numbers of GC cells were drastically reduced in LRFF/Fmb1-Cre mice. Residual LRF-deficient GC B cells were mostly negative for CXCR4, which is predominantly expressed in proliferating centroblasts within GCs, suggesting that LRF-deficient GC B cells may have defects in cellular proliferation in response to antigen stimuli. Our data indicates that LRF plays key roles in mature B cell development in the secondary lymphoid organs, but dispensable for the maintenance of early BM B cells.

A Critical Role of Mir-9 in Myelopoesis and EVI1-Induced Leukemogenesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2332-2332
Author(s):  
Vitalyi Senyuk ◽  
Yunyuan Zhang ◽  
Yang Liu ◽  
Ming Ming ◽  
Jianjun Chen ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Ectopic Expression ◽  
Myeloid Differentiation ◽  
Dna Hypermethylation ◽  
Hematopoietic Stem

Abstract Abstract 2332 MicroRNA-9 (miR-9) is required for normal neurogenesis and organ development. The expression of miR-9 is altered in several types of solid tumors suggesting that it may have a function in cell transformation. However the role of this miR in normal hematopoiesis and leukemogenesis is unknown. Here we show that miR-9 is expressed at low levels in hematopoietic stem/progenitor cells (HSCs/HPCs), and that it is upregulated during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis, while promoting apoptosis in vitro and in vivo. In addition, the inhibition of miR-9 in HPC with a miRNA sponge blocks myelopoiesis. EVI1, required for normal embryogenesis, and is considered an oncogene because inappropriate upregulation induces malignant transformation in solid and hematopoietic cancers. In vitro, EVI1 severely affects myeloid differentiation. Here we show that EVI1 binds to the promoter of miR-9–3 leading to DNA hypermethylation of the promoter as well as repression of miR-9. We also show that ectopic miR-9 reverses the myeloid differentiation block that is induced by EVI1. Our findings suggest that inappropriately expressed EVI1 delays or blocks myeloid differentiation, at least in part by DNA hypermethylation and downregulation of miR-9. It was previously reported that FoxOs genes inhibit myeloid differentiation and prevent differentiation of leukemia initiating cells. Here we identify FoxO3 and FoxO1 as new direct targets of miR-9 in hematopoietic cells, and we find that upregulation of FoxO3 in miR-9-positive cells reduces the acceleration of myelopoiesis. These results reveal a novel role of miR-9 in myelopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms. They also provide new insights on the potential chromatin-modifying role of oncogenes in epigenetic changes in cancer cells. Disclosures: No relevant conflicts of interest to declare.

The Bcl6 RD2 Domain Is Essential For Pre-Germinal Center B Cell Development

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 783-783
Author(s):  
Chuanxin Huang ◽  
Ann Haberman ◽  
Ari M. Melnick
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Transcriptional Repression ◽  
Cell Development ◽  
B Cell Development ◽  
Wild Type ◽  
Btb Domain ◽  
Repression Domain

Abstract The transcriptional repressor Bcl6 is a master regulator of the germinal center (GC) reaction through directing naïve B cells and CD4+ T cells to differentiate into GC B cells and follicular T helper (TFH) cells respectively. Bcl6 mediates its action largely by recruitment of co-repressors through its N-terminal BTB domain and its middle second repression domain (RD2). The BTB domain repression function is critical for GC B cell survival and proliferation, but not important for TFH cell differentiation. However, the in vivobiological function of RD2 remains unknown. To explore the specific role of RD2 transcriptional repression in the GC reaction, we generated a knockin mouse model in which the endogenous Bcl6 locus encodes a mutant form of the protein that specifically disrupts RD2 mediated transcriptional repression. RD2 mutant mice were developmentally indistinguishable from wild-type mice and displayed normal B cell development prior to the GC phase. However, these mice failed to accumulate GCs after immunization with sheep blood cells and exhibited remarkably impaired production of high-affinity antibodies 21 days after T-cell dependent antigen immunization, indicative of severe deficiency of the GC reaction. Mixed bone marrow transplantation experiments showed that RD2 loss of function led to complete loss of GC B cells and partial impairment of TFH cell differentiation in cell-intrinsic manner. Intravital imaging analysis indicated that RD2-deficent antigen-engaged B cells migrate normally to the inter-follicular zone of lymph nodes and interacted normally with cognate T helper cells. To further understand the nature of the functional defect of RD2 mutant B-cells, hen egg lysosome (HEL)-specific RD2-deficient GFP B cells and wild type RFP B cells (with the ratio 1:1) were transferred together with non-fluorescent ovalbumin (OVA)-specific T cells into SMARTA hosts, which were then immunized at the footpad with HEL-OVA two days later. On day 5 after immunization, draining popliteal lymph nodes were harvested and subjected for immunofluorescence histology analysis. At this time point, wild-type RFP B cells have started to cluster into tiny GC, whereas RD2-deficient GFP B cells did not form GCs. Moreover, wild-type B cells in the follicular interior were predominantly Bcl6hi, a characteristic of pre-GC B cells, suggesting that they could serve as a source of GC B cells. By contrast, RD2-deficient GFP B cells were primarily extra-follicular, and infrequently observed in the follicle interior. Most importantly, these cells were typically Bcl6lo, demonstrating that RD2 repression function is essential for pre-GC B cell differentiation. BCL6 knockout mice display a lethal inflammatory phenotype due to aberrant T-cell and macrophage activation. In striking contrast, RD2-deficient mice experienced normal healthy lives with no inflammation, and had nearly normal inflammation cytokine production in B cells and macrophages as well as differentiation of Th1,Th2 and Th17 subtypes. Hence the RD2 repression domain is specifically involved in humoral immunity but has minimal participation in the anti-inflammatory functions of BCL6. Instead we observed that the BCL6 zing finger domain plays the key role in anti-inflammatory functions in macrophages, and through ChIP-competition assays show that this is mediated by directly competing with STATs for binding to chemokine genes. These results highlight an essential role of RD2-mediated transcriptional repression in pre-GC B cell development specifically at the early B-cell activation phase. This is different than mice with BCL6 BTB mutations where early activation is normal and the defect occurs later on in the proliferative phase of GCs. The data suggest a surprising development and cellular context-specific biochemical functions of Bcl6 governing each distinct phase of the humoral immune response and inflammation. Disclosures: No relevant conflicts of interest to declare.

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