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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.
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13 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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27 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: 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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19 MeSH Terms
Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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MeSH Terms
Alpha to Beta Cell Reprogramming: Stepping toward a New Treatment for Diabetes.
Osipovich AB, Magnuson MA
(2018) Cell Stem Cell 22: 12-13
MeSH Terms: Animals, Cellular Reprogramming, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Homeodomain Proteins, Insulin, Insulin-Secreting Cells, Mice, Pancreatic Ducts
Show Abstract · Added January 8, 2018
Beta cell replacement strategies hold promise for permanently treating type 1 diabetes. In Cell Stem Cell, Xiao et al. (2018) restore pancreatic beta cell mass and normalize blood glucose in diabetic mice by reprogramming pancreatic alpha to beta cells using Pdx1- and Mafa-expressing adeno-associated virus infused into the pancreatic duct.
Copyright © 2017 Elsevier Inc. All rights reserved.
2 Communities
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9 MeSH Terms
Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.
O'Brien BMJ, Palumbos SD, Novakovic M, Shang X, Sundararajan L, Miller DM
(2017) Dev Biol 432: 248-257
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, DNA-Binding Proteins, Dendrites, Gene Expression Regulation, LIM-Homeodomain Proteins, Membrane Proteins, Nociceptors, Regulatory Elements, Transcriptional, Sensory Receptor Cells, Transcription Factors, Zinc Fingers
Show Abstract · Added March 26, 2019
The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors.
Cogger KF, Sinha A, Sarangi F, McGaugh EC, Saunders D, Dorrell C, Mejia-Guerrero S, Aghazadeh Y, Rourke JL, Screaton RA, Grompe M, Streeter PR, Powers AC, Brissova M, Kislinger T, Nostro MC
(2017) Nat Commun 8: 331
MeSH Terms: Biomarkers, Tumor, Cell Differentiation, Cell Membrane, Cells, Cultured, GPI-Linked Proteins, Homeodomain Proteins, Humans, Insulin-Secreting Cells, Mass Spectrometry, Pancreas, Pluripotent Stem Cells, Proteomics, Stem Cells, Trans-Activators, Transcription Factors
Show Abstract · Added March 21, 2018
PDX1/NKX6-1 pancreatic progenitors (PPs) give rise to endocrine cells both in vitro and in vivo. This cell population can be successfully differentiated from human pluripotent stem cells (hPSCs) and hold the potential to generate an unlimited supply of β cells for diabetes treatment. However, the efficiency of PP generation in vitro is highly variable, negatively impacting reproducibility and validation of in vitro and in vivo studies, and consequently, translation to the clinic. Here, we report the use of a proteomics approach to phenotypically characterize hPSC-derived PPs and distinguish these cells from non-PP populations during differentiation. Our analysis identifies the pancreatic secretory granule membrane major glycoprotein 2 (GP2) as a PP-specific cell surface marker. Remarkably, GP2 is co-expressed with NKX6-1 and PTF1A in human developing pancreata, indicating that it marks the multipotent pancreatic progenitors in vivo. Finally, we show that isolated hPSC-derived GP2 cells generate β-like cells (C-PEPTIDE/NKX6-1) more efficiently compared to GP2 and unsorted populations, underlining the potential therapeutic applications of GP2.Pancreatic progenitors (PPs) can be derived from human pluripotent stem cells in vitro but efficiency of differentiation varies, making it hard to sort for insulin-producing cells. Here, the authors use a proteomic approach to identify the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ PPs.
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15 MeSH Terms
Defining a Novel Role for the Pdx1 Transcription Factor in Islet β-Cell Maturation and Proliferation During Weaning.
Spaeth JM, Gupte M, Perelis M, Yang YP, Cyphert H, Guo S, Liu JH, Guo M, Bass J, Magnuson MA, Wright C, Stein R
(2017) Diabetes 66: 2830-2839
MeSH Terms: Animals, Cell Proliferation, Gene Expression Regulation, Homeodomain Proteins, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Oxidative Phosphorylation, Trans-Activators, Weaning
Show Abstract · Added August 1, 2017
The transcription factor encoded by the gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β-cell development, and adult islet β-cell function. Transgenic- and cell line-based experiments have identified 5'-flanking conserved sequences that control pancreatic and β-cell type-specific transcription, which are found within areas I (bp -2694 to -2561), II (bp -2139 to -1958), III (bp -1879 to -1799), and IV (bp -6200 to -5670). Because of the presence in area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected expression embryonically and postnatally. The most striking result was observed in male mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β-cells were tightly linked with hyperglycemia, decreased β-cell proliferation, reduced β-cell area, and altered expression of Pdx1-bound genes that are important in β-cell replication, endoplasmic reticulum function, and mitochondrial activity. We discuss the impact of these novel findings to gene regulation and islet β-cell maturation postnatally.
© 2017 by the American Diabetes Association.
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11 MeSH Terms
The major miR-31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation.
Luan L, Shi J, Yu Z, Andl T
(2017) Exp Dermatol 26: 497-504
MeSH Terms: 3' Untranslated Regions, Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Carcinoma, Basal Cell, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cell Survival, Hair Follicle, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Keratinocytes, Mice, Mice, Transgenic, MicroRNAs, Protein-Serine-Threonine Kinases, Skin, Skin Neoplasms, Transcription Factors, Tumor Suppressor Proteins
Show Abstract · Added June 21, 2017
Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR-31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non-melanoma skin cancer and hair follicle growth. miR-31 is a marker of the hair growth phase, and in our miR-31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR-31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR-31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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22 MeSH Terms
The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity.
Kim Y, Lim S, Ha T, Song YH, Sohn YI, Park DJ, Paik SS, Kim-Kaneyama JR, Song MR, Leung A, Levine EM, Kim IB, Goo YS, Lee SH, Kang KH, Kim JW
(2017) Elife 6:
MeSH Terms: Adaptation, Ocular, Animals, Cytoskeletal Proteins, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, LIM Domain Proteins, LIM-Homeodomain Proteins, Mice, Mice, Knockout, PAX6 Transcription Factor, Retina, Transcription Factors
Show Abstract · Added February 14, 2018
The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.
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13 MeSH Terms