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The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function.
Spaeth JM, Liu JH, Peters D, Guo M, Osipovich AB, Mohammadi F, Roy N, Bhushan A, Magnuson MA, Hebrok M, Wright CVE, Stein R
(2019) Diabetes 68: 1806-1818
MeSH Terms: Animals, Cell Proliferation, Chromatin Assembly and Disassembly, DNA Helicases, Gene Expression Regulation, Glucose Intolerance, Homeodomain Proteins, Insulin, Insulin-Secreting Cells, Mice, Mice, Transgenic, Nuclear Proteins, Pancreas, Trans-Activators, Transcription Factors
Show Abstract · Added June 28, 2019
Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β-cells lost the ability to produce the mRNAs for and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas, and we discuss how disrupting their association could influence type 1 and type 2 diabetes susceptibility.
© 2019 by the American Diabetes Association.
1 Communities
3 Members
0 Resources
15 MeSH Terms
B lymphocytes protect islet β cells in diabetes prone NOD mice treated with imatinib.
Wilson CS, Spaeth JM, Karp J, Stocks BT, Hoopes EM, Stein RW, Moore DJ
(2019) JCI Insight 5:
MeSH Terms: Animals, Autoimmunity, B-Lymphocytes, Cell Proliferation, Diabetes Mellitus, Type 1, Disease Models, Animal, Homeodomain Proteins, Hyperglycemia, Imatinib Mesylate, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Maf Transcription Factors, Large, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout
Show Abstract · Added April 10, 2019
Imatinib (Gleevec) reverses type 1 diabetes (T1D) in NOD mice and is currently in clinical trials in individuals with recent-onset disease. While research has demonstrated that imatinib protects islet β cells from the harmful effects of ER stress, the role the immune system plays in its reversal of T1D has been less well understood, and specific cellular immune targets have not been identified. In this study, we demonstrate that B lymphocytes, an immune subset that normally drives diabetes pathology, are unexpectedly required for reversal of hyperglycemia in NOD mice treated with imatinib. In the presence of B lymphocytes, reversal was linked to an increase in serum insulin concentration, but not an increase in islet β cell mass or proliferation. However, improved β cell function was reflected by a partial recovery of MafA transcription factor expression, a sensitive marker of islet β cell stress that is important to adult β cell function. Imatinib treatment was found to increase the antioxidant capacity of B lymphocytes, improving reactive oxygen species (ROS) handling in NOD islets. This study reveals a novel mechanism through which imatinib enables B lymphocytes to orchestrate functional recovery of T1D β cells.
0 Communities
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17 MeSH Terms
Point mutations in the PDX1 transactivation domain impair human β-cell development and function.
Wang X, Sterr M, Ansarullah , Burtscher I, Böttcher A, Beckenbauer J, Siehler J, Meitinger T, Häring HU, Staiger H, Cernilogar FM, Schotta G, Irmler M, Beckers J, Wright CVE, Bakhti M, Lickert H
(2019) Mol Metab 24: 80-97
MeSH Terms: Adult, Carboxylic Ester Hydrolases, Cell Differentiation, Cell Line, Diabetes Mellitus, Female, Homeodomain Proteins, Humans, Insulin Secretion, Insulin-Secreting Cells, Loss of Function Mutation, Male, Point Mutation, Protein Domains, RNA, Long Noncoding, Trans-Activators, Transcription Factors
Show Abstract · Added April 2, 2019
OBJECTIVE - Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown.
METHODS - In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1, PDX1 mutations and engineered isogenic cell lines carrying homozygous PDX1, PDX1 mutations and a heterozygous PDX1 loss-of-function mutation (PDX1).
RESULTS - Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1, PDX1 and homozygous PDX1, PDX1 mutations impair β-cell differentiation and function. Furthermore, PDX1 and PDX1 mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1 and PDX1 mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion.
CONCLUSIONS - Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
1 Communities
1 Members
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17 MeSH Terms
Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1.
Vanslambrouck JM, Woodard LE, Suhaimi N, Williams FM, Howden SE, Wilson SB, Lonsdale A, Er PX, Li J, Maksimovic J, Oshlack A, Wilson MH, Little MH
(2019) Kidney Int 95: 1153-1166
MeSH Terms: Cells, Cultured, Cellular Reprogramming, DNA Transposable Elements, Gene Transfer Techniques, Genetic Engineering, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Nephrons, Nuclear Proteins, Primary Cell Culture, Protein Tyrosine Phosphatases, Regeneration, Snail Family Transcription Factors
Show Abstract · Added March 28, 2019
All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost close to the time of birth. The generation of new nephron progenitors and their maintenance in culture are central to the success of kidney regenerative strategies. Using a lentiviral screening approach, we previously generated a human induced nephron progenitor-like state in vitro using a pool of six transcription factors. Here, we sought to develop a more efficient approach for direct reprogramming of human cells that could be applied in vivo. PiggyBac transposons are a non-viral integrating gene delivery system that is suitable for in vivo use and allows for simultaneous delivery of multiple genes. Using an inducible piggyBac transposon system, we optimized a protocol for the direct reprogramming of HK2 cells to induced nephron progenitor-like cells with expression of only 3 transcription factors (SNAI2, EYA1, and SIX1). Culture in conditions supportive of the nephron progenitor state further increased the expression of nephron progenitor genes. The refined protocol was then applied to primary human renal epithelial cells, which integrated into developing nephron structures in vitro and in vivo. Such inducible reprogramming to nephron progenitor-like cells could facilitate direct cellular reprogramming for kidney regeneration.
Copyright © 2019 International Society of Nephrology. All rights reserved.
0 Communities
2 Members
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14 MeSH Terms
Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.
Fleming JT, Brignola E, Chen L, Guo Y, Zhao S, Wang Q, Li B, Correa H, Ermilov AN, Dlugosz AA, Chiang C
(2019) Mol Cancer Res 17: 1024-1035
MeSH Terms: Animals, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Homeodomain Proteins, Humans, Mice, Neoplasm Transplantation, Nerve Tissue Proteins, Sarcoma, Ewing, Signal Transduction, Zebrafish Proteins, Zinc Finger Protein Gli3
Show Abstract · Added April 10, 2019
Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by gene fusions, a genetically defined mouse model is not well-established. While gene fusions were not present in sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known gene targets essential to Ewing pathogenesis, most notably, . Moreover, we found that naïve mesenchymal progenitors originate tumors in mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. IMPLICATIONS: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.
©2019 American Association for Cancer Research.
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1 Members
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12 MeSH Terms
Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
(2019) Dev Cell 48: 49-63.e7
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Endocrine Cells, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Transcription Factors
Show Abstract · Added February 6, 2019
In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; when and how the Neurog3 cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3 cells co-expressing Myt1 (i.e., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.
Published by Elsevier Inc.
1 Communities
1 Members
0 Resources
13 MeSH Terms
LNK deficiency promotes acute aortic dissection and rupture.
Laroumanie F, Korneva A, Bersi MR, Alexander MR, Xiao L, Zhong X, Van Beusecum JP, Chen Y, Saleh MA, McMaster WG, Gavulic KA, Dale BL, Zhao S, Guo Y, Shyr Y, Perrien DS, Cox NJ, Curci JA, Humphrey JD, Madhur MS
(2018) JCI Insight 3:
MeSH Terms: Adaptor Proteins, Signal Transducing, Aneurysm, Dissecting, Angiotensin II, Animals, Aorta, Aortic Rupture, Disease Models, Animal, Female, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Male, Mice, Mice, Knockout
Show Abstract · Added April 1, 2019
Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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1 Members
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27 MeSH Terms
VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
(2018) Science 361: 290-295
MeSH Terms: Animals, Carcinoma, Renal Cell, Chromatin Immunoprecipitation, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Hydroxylation, Kidney Neoplasms, Mice, Mice, SCID, Molecular Targeted Therapy, Mutation, NF-kappa B, Oncogenes, Substrate Specificity, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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MeSH Terms
Genome-wide analysis of PDX1 target genes in human pancreatic progenitors.
Wang X, Sterr M, Burtscher I, Chen S, Hieronimus A, Machicao F, Staiger H, Häring HU, Lederer G, Meitinger T, Cernilogar FM, Schotta G, Irmler M, Beckers J, Hrabě de Angelis M, Ray M, Wright CVE, Bakhti M, Lickert H
(2018) Mol Metab 9: 57-68
MeSH Terms: Calcium-Binding Proteins, Cell Differentiation, Cells, Cultured, Chromatin Assembly and Disassembly, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Insulin-Secreting Cells, Intercellular Signaling Peptides and Proteins, Membrane Proteins, Myeloid Ecotropic Viral Integration Site 1 Protein, Polymorphism, Single Nucleotide, Protein Binding, Regulatory Factor X Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein
Show Abstract · Added February 6, 2018
OBJECTIVE - Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far.
METHODS - In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions.
RESULTS - ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes.
CONCLUSIONS - Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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20 MeSH Terms