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FUCCI tracking shows cell-cycle-dependent Neurog3 variation in pancreatic progenitors.
Bechard ME, Bankaitis ED, Ustione A, Piston DW, Magnuson MA, Wright CVE
(2017) Genesis 55:
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cells, Cultured, Embryonic Stem Cells, Green Fluorescent Proteins, Islets of Langerhans, Mice, Nerve Tissue Proteins
Show Abstract · Added September 5, 2017
During pancreas organogenesis, Neurog3 endocrine-committing cells are generated from a population of Sox9 mitotic progenitors with only a low level of Neurog3 transcriptional activity (Neurog3 ). Low-level Neurog3 protein, in Neurog3 cells, is required to maintain their mitotic endocrine-lineage-primed status. Herein, we describe a Neurog3-driven FUCCI cell-cycle reporter (Neurog3 ) derived from a Neurog3 BAC transgenic reporter that functions as a loxed cassette acceptor (LCA). In cycling Sox9 Neurog3 progenitors, the majority of cells in S-G -M phases have undetectable levels of Neurog3 with increased expression of endocrine progenitor markers, while those in G have low Neurog3 levels with increased expression of endocrine differentiation markers. These findings support a model in which variations in Neurog3 protein levels are coordinated with cell-cycle phase progression in Neurog3 progenitors with entrance into G triggering a concerted effort, beyond increasing Neurog3 levels, to maintain an endocrine-lineage-primed state by initiating expression of the downstream endocrine differentiation program prior to endocrine-commitment.
© 2017 Wiley Periodicals, Inc.
3 Communities
1 Members
0 Resources
9 MeSH Terms
The Molecular Basis for the Lack of Inflammatory Responses in Mouse Embryonic Stem Cells and Their Differentiated Cells.
D'Angelo W, Gurung C, Acharya D, Chen B, Ortolano N, Gama V, Bai F, Guo YL
(2017) J Immunol 198: 2147-2155
MeSH Terms: Animals, Cell Differentiation, Chikungunya Fever, Chikungunya virus, Embryonic Stem Cells, Immunity, Inflammation, Interferons, Lipopolysaccharides, Mice, Mice, Inbred DBA, NF-kappa B, RAW 264.7 Cells, Tumor Necrosis Factor-alpha, Virus Diseases
Show Abstract · Added July 10, 2017
We reported previously that mouse embryonic stem cells do not have a functional IFN-based antiviral mechanism. The current study extends our investigation to the inflammatory response in mouse embryonic stem cells and mouse embryonic stem cell-differentiated cells. We demonstrate that LPS, TNF-α, and viral infection, all of which induce robust inflammatory responses in naturally differentiated cells, failed to activate NF-κB, the key transcription factor that mediates inflammatory responses, and were unable to induce the expression of inflammatory genes in mouse embryonic stem cells. Similar results were obtained in human embryonic stem cells. In addition to the inactive state of NF-κB, the deficiency in the inflammatory response in mouse embryonic stem cells is also attributed to the lack of functional receptors for LPS and TNF-α. In vitro differentiation can trigger the development of the inflammatory response mechanism, as indicated by the transition of NF-κB from its inactive to active state. However, a limited response to TNF-α and viral infection, but not to LPS, was observed in mouse embryonic stem cell-differentiated fibroblasts. We conclude that the inflammatory response mechanism is not active in mouse embryonic stem cells, and in vitro differentiation promotes only partial development of this mechanism. Together with our previous studies, the findings described in this article demonstrate that embryonic stem cells are fundamentally different from differentiated somatic cells in their innate immunity, which may have important implications in developmental biology, immunology, and embryonic stem cell-based regenerative medicine.
Copyright © 2017 by The American Association of Immunologists, Inc.
0 Communities
1 Members
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15 MeSH Terms
Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.
Osipovich AB, Gangula R, Vianna PG, Magnuson MA
(2016) Development 143: 4595-4607
MeSH Terms: Acetylation, Animals, Apoptosis, Carrier Proteins, Cell Cycle, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chromatin, Embryonic Development, Embryonic Stem Cells, Gene Expression Regulation, Heart Defects, Congenital, Histones, Methyltransferases, Mice, Mice, Knockout, Myocytes, Cardiac, Neural Tube, Promoter Regions, Genetic, RNA, Untranslated, Transcription, Genetic
Show Abstract · Added November 30, 2016
SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.
© 2016. Published by The Company of Biologists Ltd.
2 Communities
2 Members
0 Resources
22 MeSH Terms
Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.
Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV
(2015) Nat Commun 6: 8715
MeSH Terms: Cell Differentiation, Clustered Regularly Interspaced Short Palindromic Repeats, Embryonic Stem Cells, Gene Knockout Techniques, Germ Layers, Humans, Kidney, Kidney Diseases, Models, Biological, Organoids, Pluripotent Stem Cells, Sialoglycoproteins
Show Abstract · Added September 12, 2016
Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.
1 Communities
1 Members
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12 MeSH Terms
A Gene Regulatory Network Cooperatively Controlled by Pdx1 and Sox9 Governs Lineage Allocation of Foregut Progenitor Cells.
Shih HP, Seymour PA, Patel NA, Xie R, Wang A, Liu PP, Yeo GW, Magnuson MA, Sander M
(2015) Cell Rep 13: 326-36
MeSH Terms: Animals, Cell Lineage, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Homeodomain Proteins, Intestinal Mucosa, Intestines, Mice, Pancreas, SOX9 Transcription Factor, Trans-Activators, Transcriptional Activation
Show Abstract · Added November 3, 2015
The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
1 Members
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13 MeSH Terms
PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells.
Teo AK, Tsuneyoshi N, Hoon S, Tan EK, Stanton LW, Wright CV, Dunn NR
(2015) Stem Cell Reports 4: 578-90
MeSH Terms: Binding Sites, Biomarkers, Cell Differentiation, Cell Line, Cluster Analysis, Computational Biology, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Human Embryonic Stem Cells, Humans, Liver, Nucleotide Motifs, Organ Specificity, Organogenesis, Pancreas, Position-Specific Scoring Matrices, Protein Binding, Response Elements, Trans-Activators, Transcription, Genetic
Show Abstract · Added April 7, 2015
Inactivation of the Pancreatic and Duodenal Homeobox 1 (PDX1) gene causes pancreatic agenesis, which places PDX1 high atop the regulatory network controlling development of this indispensable organ. However, little is known about the identity of PDX1 transcriptional targets. We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq). We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation. This group included known PDX1 targets and many genes not previously linked to pancreatic development. ChIP-seq also revealed PDX1 occupancy at hepatic genes. We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver. In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes. These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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21 MeSH Terms
Extrapolating histone marks across developmental stages, tissues, and species: an enhancer prediction case study.
Capra JA
(2015) BMC Genomics 16: 104
MeSH Terms: Acetylation, Animals, Cell Differentiation, Embryonic Development, Embryonic Stem Cells, Enhancer Elements, Genetic, Epigenomics, Gene Expression Regulation, Developmental, Heart, Histone Code, Histones, Humans, Machine Learning, Mice
Show Abstract · Added February 22, 2016
BACKGROUND - Dynamic activation and inactivation of gene regulatory DNA produce the expression changes that drive the differentiation of cellular lineages. Identifying regulatory regions active during developmental transitions is necessary to understand how the genome specifies complex developmental programs and how these processes are disrupted in disease. Gene regulatory dynamics are mediated by many factors, including the binding of transcription factors (TFs) and the methylation and acetylation of DNA and histones. Genome-wide maps of TF binding and DNA and histone modifications have been generated for many cellular contexts; however, given the diversity and complexity of animal development, these data cover only a small fraction of the cellular and developmental contexts of interest. Thus, there is a need for methods that use existing epigenetic and functional genomics data to analyze the thousands of contexts that remain uncharacterized.
RESULTS - To investigate the utility of histone modification data in the analysis of cellular contexts without such data, I evaluated how well genome-wide H3K27ac and H3K4me1 data collected in different developmental stages, tissues, and species were able to predict experimentally validated heart enhancers active at embryonic day 11.5 (E11.5) in mouse. Using a machine-learning approach to integrate the data from different contexts, I found that E11.5 heart enhancers can often be predicted accurately from data from other contexts, and I quantified the contribution of each data source to the predictions. The utility of each dataset correlated with nearness in developmental time and tissue to the target context: data from late developmental stages and adult heart tissues were most informative for predicting E11.5 enhancers, while marks from stem cells and early developmental stages were less informative. Predictions based on data collected in non-heart tissues and in human hearts were better than random, but worse than using data from mouse hearts.
CONCLUSIONS - The ability of these algorithms to accurately predict developmental enhancers based on data from related, but distinct, cellular contexts suggests that combining computational models with epigenetic data sampled from relevant contexts may be sufficient to enable functional characterization of many cellular contexts of interest.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Spatial regionalization and heterochrony in the formation of adult pallial neural stem cells.
Dirian L, Galant S, Coolen M, Chen W, Bedu S, Houart C, Bally-Cuif L, Foucher I
(2014) Dev Cell 30: 123-36
MeSH Terms: Adult Stem Cells, Animals, Cell Lineage, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Globus Pallidus, Neural Stem Cells, Neurogenesis, Neuroglia, Neurons, Organ Specificity, Promoter Regions, Genetic, Transcription, Genetic, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 12, 2015
Little is known on the embryonic origin and related heterogeneity of adult neural stem cells (aNSCs). We use conditional genetic tracing, activated in a global or mosaic fashion by cell type-specific promoters or focal laser uncaging, coupled with gene expression analyses and Notch invalidations, to address this issue in the zebrafish adult telencephalon. We report that the germinal zone of the adult pallium originates from two distinct subtypes of embryonic progenitors and integrates two modes of aNSC formation. Dorsomedial aNSCs derive from the amplification of actively neurogenic radial glia of the embryonic telencephalon. On the contrary, the lateral aNSC population is formed by stepwise addition at the pallial edge from a discrete neuroepithelial progenitor pool of the posterior telencephalic roof, activated at postembryonic stages and persisting lifelong. This dual origin of the pallial germinal zone allows the temporally organized building of pallial territories as a patchwork of juxtaposed compartments.
Copyright © 2014 Elsevier Inc. All rights reserved.
0 Communities
1 Members
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15 MeSH Terms
Resident progenitors, not exogenous migratory cells, generate the majority of visceral mesothelium in organogenesis.
Winters NI, Williams AM, Bader DM
(2014) Dev Biol 391: 125-32
MeSH Terms: Animals, Cell Differentiation, Cell Movement, Chick Embryo, Chimera, Embryonic Stem Cells, Epithelium, Gastrointestinal Tract, Heart, Organogenesis, Quail, Respiratory System
Show Abstract · Added September 28, 2015
Historically, analyses of mesothelial differentiation have focused on the heart where a highly migratory population of progenitors originating from a localized "extrinsic" source moves to and over the developing organ. This model long stood alone as the paradigm for generation of this cell type. Here, using chick/quail chimeric grafting and subsequent identification of mesothelial cell populations, we demonstrate that a different mechanism for the generation of mesothelia exists in vertebrate organogenesis. In this newly discovered model, mesothelial progenitors are intrinsic to organs of the developing digestive and respiratory systems. Additionally, we demonstrate that the early heart stands alone in its ability to recruit an entirely exogenous mesothelial cell layer during development. Thus, the newly identified "organ intrinsic" model of mesotheliogenesis appears to predominate while the long-studied cardiac model of mesothelial development may be the outlier.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
12 MeSH Terms
Gremlin 2 promotes differentiation of embryonic stem cells to atrial fate by activation of the JNK signaling pathway.
Tanwar V, Bylund JB, Hu J, Yan J, Walthall JM, Mukherjee A, Heaton WH, Wang WD, Potet F, Rai M, Kupershmidt S, Knapik EW, Hatzopoulos AK
(2014) Stem Cells 32: 1774-88
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, Embryonic Stem Cells, Heart Atria, MAP Kinase Signaling System, Mice, Myocytes, Cardiac, Proteins
Show Abstract · Added May 27, 2014
The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for atrial differentiation and establishment of cardiac rhythm during embryonic development. A human Grem2 variant has been associated with familial atrial fibrillation, suggesting that abnormal Grem2 activity causes arrhythmias. However, it is not known how Grem2 integrates into signaling pathways to direct atrial cardiomyocyte differentiation. Here, we demonstrate that Grem2 expression is induced concurrently with the emergence of cardiovascular progenitor cells during differentiation of mouse embryonic stem cells (ESCs). Grem2 exposure enhances the cardiogenic potential of ESCs by 20-120-fold, preferentially inducing genes expressed in atrial myocytes such as Myl7, Nppa, and Sarcolipin. We show that Grem2 acts upstream to upregulate proatrial transcription factors CoupTFII and Hey1 and downregulate atrial fate repressors Irx4 and Hey2. The molecular phenotype of Grem2-induced atrial cardiomyocytes was further supported by induction of ion channels encoded by Kcnj3, Kcnj5, and Cacna1d genes and establishment of atrial-like action potentials shown by electrophysiological recordings. We show that promotion of atrial-like cardiomyocytes is specific to the Gremlin subfamily of BMP antagonists. Grem2 proatrial differentiation activity is conveyed by noncanonical BMP signaling through phosphorylation of JNK and can be reversed by specific JNK inhibitors, but not by dorsomorphin, an inhibitor of canonical BMP signaling. Taken together, our data provide novel mechanistic insights into atrial cardiomyocyte differentiation from pluripotent stem cells and will assist the development of future approaches to study and treat arrhythmias.
© 2014 AlphaMed Press.
1 Communities
2 Members
0 Resources
9 MeSH Terms