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Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones.
Iwafuchi M, Cuesta I, Donahue G, Takenaka N, Osipovich AB, Magnuson MA, Roder H, Seeholzer SH, Santisteban P, Zaret KS
(2020) Nat Genet 52: 418-427
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Chromatin, DNA, Female, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Histones, Humans, Mice, Mice, Inbred C57BL, Nucleosomes, Transcription Factors, Transcription, Genetic
Show Abstract · Added April 7, 2020
Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. However, a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short α-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming.
1 Communities
3 Members
0 Resources
15 MeSH Terms
Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.
Wooten DJ, Groves SM, Tyson DR, Liu Q, Lim JS, Albert R, Lopez CF, Sage J, Quaranta V
(2019) PLoS Comput Biol 15: e1007343
MeSH Terms: Algorithms, Animals, Basic Helix-Loop-Helix Transcription Factors, Bayes Theorem, Cell Line, Tumor, Cluster Analysis, Databases, Genetic, Drug Resistance, Neoplasm, Gene Expression, Gene Expression Regulation, Neoplastic, Gene Ontology, Gene Regulatory Networks, Humans, Mice, Models, Theoretical, Small Cell Lung Carcinoma, Systems Analysis, Transcription Factors
Show Abstract · Added March 30, 2020
Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes (SCLC-A, SCLC-N, and SCLC-Y), while the fourth is a previously undescribed ASCL1+ neuroendocrine variant (NEv2, or SCLC-A2). Tumor deconvolution with subtype gene signatures shows that all of the subtypes are detectable in varying proportions in human and mouse tumors. To understand how multiple stable subtypes can arise within a tumor, we infer a network of transcription factors and develop BooleaBayes, a minimally-constrained Boolean rule-fitting approach. In silico perturbations of the network identify master regulators and destabilizers of its attractors. Specific to NEv2, BooleaBayes predicts ELF3 and NR0B1 as master regulators of the subtype, and TCF3 as a master destabilizer. Since the four subtypes exhibit differential drug sensitivity, with NEv2 consistently least sensitive, these findings may lead to actionable therapeutic strategies that consider SCLC intratumoral heterogeneity. Our systems-level approach should generalize to other cancer types.
0 Communities
1 Members
0 Resources
MeSH Terms
Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway.
Gobert AP, Latour YL, Asim M, Finley JL, Verriere TG, Barry DP, Milne GL, Luis PB, Schneider C, Rivera ES, Lindsey-Rose K, Schey KL, Delgado AG, Sierra JC, Piazuelo MB, Wilson KT
(2019) mBio 10:
MeSH Terms: Animals, Bacteria, Gene Silencing, Helicobacter pylori, Histones, Humans, Immune Evasion, Immunity, Innate, Immunoglobulins, Macrophages, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, Phosphatidylinositol 3-Kinases, Polyamines, RAW 264.7 Cells, Spermidine, Spermine, Sulfur, Transcription Factors
Show Abstract · Added November 1, 2019
The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of -adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism.
Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC
(2019) Dev Cell 50: 744-754.e4
MeSH Terms: Acinar Cells, Animals, Carcinogenesis, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Clone Cells, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Inflammation, Mice, Pancreatic Neoplasms, Pancreatitis, Phenotype, Proto-Oncogene Proteins p21(ras), Signal Transduction, Transcription Factors
Show Abstract · Added September 3, 2019
Activating mutations in Kras are nearly ubiquitous in human pancreatic cancer and initiate precancerous pancreatic intraepithelial neoplasia (PanINs) when induced in mouse acinar cells. PanINs normally take months to form but are accelerated by deletion of acinar cell differentiation factors such as Ptf1a, suggesting that loss of cell identity is rate limiting for pancreatic tumor initiation. Using a genetic mouse model that allows for independent control of oncogenic Kras and Ptf1a expression, we demonstrate that sustained Ptf1a is sufficient to prevent Kras-driven tumorigenesis, even in the presence of tumor-promoting inflammation. Furthermore, reintroducing Ptf1a into established PanINs reverts them to quiescent acinar cells in vivo. Similarly, Ptf1a re-expression in human pancreatic cancer cells inhibits their growth and colony-forming ability. Our results suggest that reactivation of an endogenous differentiation program can prevent and reverse oncogene-driven transformation in cells harboring tumor-driving mutations, introducing a potential paradigm for solid tumor prevention and treatment.
Copyright © 2019 Elsevier Inc. All rights reserved.
1 Communities
0 Members
0 Resources
18 MeSH Terms
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
Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein.
Plate L, Rius B, Nguyen B, Genereux JC, Kelly JW, Wiseman RL
(2019) Cell Chem Biol 26: 913-925.e4
MeSH Terms: Activating Transcription Factor 6, Amyloidogenic Proteins, Amyloidosis, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, HEK293 Cells, Humans, Molecular Chaperones, Proteomics, Transcription Factors, Unfolded Protein Response
Show Abstract · Added March 3, 2020
Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. We employ a quantitative interactomics platform to define how ATF6 activation reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with light-chain amyloidosis (AL). Using this platform, we show that ATF6 activation increases the targeting of this destabilized LC to a subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion. Our results define a molecular basis for the ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.
Copyright © 2019 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Myocardial differentiation is dependent upon endocardial signaling during early cardiogenesis .
Saint-Jean L, Barkas N, Harmelink C, Tompkins KL, Oakey RJ, Baldwin HS
(2019) Development 146:
MeSH Terms: Animals, Cell Differentiation, Endocardium, Female, Flow Cytometry, Male, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Myocardium, NFATC Transcription Factors, Organogenesis, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
Show Abstract · Added November 25, 2019
The endocardium interacts with the myocardium to promote proliferation and morphogenesis during the later stages of heart development. However, the role of the endocardium in early cardiac ontogeny remains under-explored. Given the shared origin, subsequent juxtaposition, and essential cell-cell interactions of endocardial and myocardial cells throughout heart development, we hypothesized that paracrine signaling from the endocardium to the myocardium is crucial for initiating early differentiation of myocardial cells. To test this, we generated an , endocardial-specific ablation model using the diphtheria toxin receptor under the regulatory elements of the genomic locus (). Early treatment of mouse embryoid bodies with diphtheria toxin efficiently ablated endocardial cells, which significantly attenuated the percentage of beating EBs in culture and expression of early and late myocardial differentiation markers. The addition of Bmp2 during endocardial ablation partially rescued myocyte differentiation, maturation and function. Therefore, we conclude that early stages of myocardial differentiation rely on endocardial paracrine signaling mediated in part by Bmp2. Our findings provide novel insight into early endocardial-myocardial interactions that can be explored to promote early myocardial development and growth.
© 2019. Published by The Company of Biologists Ltd.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Hypoxia-inducible factors in CD4 T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity.
Cho SH, Raybuck AL, Blagih J, Kemboi E, Haase VH, Jones RG, Boothby MR
(2019) Proc Natl Acad Sci U S A 116: 8975-8984
MeSH Terms: Animals, Antibody Formation, B-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors, CD4-Positive T-Lymphocytes, Cell Hypoxia, Cytokines, Germinal Center, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Humoral, Immunization, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, CXCR5, Sheep, T-Lymphocytes, Helper-Inducer
Show Abstract · Added April 23, 2019
T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4 and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4 T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4 cells in the CXCR5 follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
0 Communities
1 Members
0 Resources
20 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
1 Members
0 Resources
17 MeSH Terms
The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
0 Communities
2 Members
0 Resources
23 MeSH Terms