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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
Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS
(2019) Nat Cell Biol 21: 1532-1543
MeSH Terms: Animals, Apoptosis, Biological Transport, Cell Line, Cell Line, Tumor, Chlorides, Humans, Inflammation, Jurkat Cells, Mice, Mice, Inbred C57BL, Oxidative Stress, Phagocytes, Phagocytosis, Signal Transduction, Sodium-Potassium-Chloride Symporters, Transcription, Genetic
Show Abstract · Added March 18, 2020
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
0 Communities
1 Members
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MeSH Terms
Reoviridae transcription is more than an open-and-shut case.
Ogden K
(2019) Nat Struct Mol Biol 26: 991-993
MeSH Terms: Gene Expression Regulation, Viral, Genome, Viral, Humans, RNA, Viral, Reoviridae, Reoviridae Infections, Transcription, Genetic
Added March 3, 2020
0 Communities
1 Members
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MeSH Terms
Histone deacetylase 3 controls a transcriptional network required for B cell maturation.
Stengel KR, Bhaskara S, Wang J, Liu Q, Ellis JD, Sampathi S, Hiebert SW
(2019) Nucleic Acids Res 47: 10612-10627
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Base Sequence, Cell Differentiation, Gene Expression Regulation, Gene Regulatory Networks, Histone Deacetylase Inhibitors, Histone Deacetylases, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcription, Genetic, Up-Regulation
Show Abstract · Added October 25, 2019
Histone deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
1 Communities
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18 MeSH Terms
The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus.
Chiusa M, Hu W, Liao HJ, Su Y, Borza CM, de Caestecker MP, Skrypnyk NI, Fogo AB, Pedchenko V, Li X, Zhang MZ, Hudson BG, Basak T, Vanacore RM, Zent R, Pozzi A
(2019) J Am Soc Nephrol 30: 1605-1624
MeSH Terms: Actins, Acute Kidney Injury, Animals, Biological Transport, Cell Line, Cell Nucleus, Chromatin, Collagen Type I, Collagen Type IV, Discoidin Domain Receptor 1, Humans, Kidney Tubules, Proximal, Male, Mice, Myosin Heavy Chains, Nuclear Localization Signals, Retinoblastoma-Binding Protein 4, SEC Translocation Channels, Transcription, Genetic
Show Abstract · Added May 10, 2020
BACKGROUND - The discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors.
METHODS - To determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation.
RESULTS - We show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and -actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis.
CONCLUSIONS - These findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.
Copyright © 2019 by the American Society of Nephrology.
0 Communities
1 Members
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19 MeSH Terms
The role of polyamines in the regulation of macrophage polarization and function.
Latour YL, Gobert AP, Wilson KT
(2020) Amino Acids 52: 151-160
MeSH Terms: Animals, Cell Polarity, Humans, Macrophage Activation, Macrophages, Polyamines, Transcription, Genetic
Show Abstract · Added August 6, 2020
Naturally occurring polyamines are ubiquitously distributed and play important roles in cell development, amino acid and protein synthesis, oxidative DNA damage, proliferation, and cellular differentiation. Macrophages are essential in the innate immune response, and contribute to tissue remodeling. Naïve macrophages have two major potential fates: polarization to (1) the classical pro-inflammatory M1 defense response to bacterial pathogens and tumor cells, and (2) the alternatively activated M2 response, induced in the presence of parasites and wounding, and also implicated in the development of tumor-associated macrophages. ODC, the rate-limiting enzyme in polyamine synthesis, leads to an increase in putrescine levels, which impairs M1 gene transcription. Additionally, spermidine and spermine can regulate translation of pro-inflammatory mediators in activated macrophages. In this review, we focus on polyamines in macrophage activation patterns in the context of gastrointestinal inflammation and carcinogenesis. We seek to clarify mechanisms of innate immune regulation by polyamine metabolism and potential novel therapeutic targets.
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1 Members
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7 MeSH Terms
Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.
Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, Massion PP, Minna JD, Oliver TG, Quaranta V, Sage J, Thomas RK, Vakoc CR, Gazdar AF
(2019) Nat Rev Cancer 19: 289-297
MeSH Terms: Animals, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Lung Neoplasms, Mice, Small Cell Lung Carcinoma, Transcription Factors, Transcription, Genetic
Show Abstract · Added March 30, 2020
Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.
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Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of .
Grunenwald CM, Choby JE, Juttukonda LJ, Beavers WN, Weiss A, Torres VJ, Skaar EP
(2019) mBio 10:
MeSH Terms: Animals, Cation Transport Proteins, Disease Models, Animal, Gene Expression Regulation, Bacterial, Homeostasis, Iron, Manganese, Mice, Inbred BALB C, Microbial Viability, Oxidative Stress, Staphylococcal Infections, Staphylococcus aureus, Transcription Factors, Transcription, Genetic, Virulence
Show Abstract · Added April 2, 2019
Manganese (Mn) is an essential micronutrient critical for the pathogenesis of , a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in , MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the Mn uptake system. Inactivation of or leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, and are required for full virulence of during infection, suggesting experiences Mn toxicity Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of and induction of , both of which are critical for pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of leads to a significant reduction in resistance to oxidative stress and mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and virulence. Therefore, this establishes MntE as a potential target for development of anti- therapeutics.
Copyright © 2019 Grunenwald et al.
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1 Members
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15 MeSH Terms
Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.
Haliyur R, Tong X, Sanyoura M, Shrestha S, Lindner J, Saunders DC, Aramandla R, Poffenberger G, Redick SD, Bottino R, Prasad N, Levy SE, Blind RD, Harlan DM, Philipson LH, Stein RW, Brissova M, Powers AC
(2019) J Clin Invest 129: 246-251
MeSH Terms: Adolescent, Adult, Diabetes Mellitus, Type 1, Genetic Variation, Hepatocyte Nuclear Factor 1-alpha, Heterozygote, Humans, Insulin-Secreting Cells, Male, Transcription, Genetic
Show Abstract · Added December 7, 2018
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
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4 Members
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10 MeSH Terms
Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks.
Galligan JJ, Wepy JA, Streeter MD, Kingsley PJ, Mitchener MM, Wauchope OR, Beavers WN, Rose KL, Wang T, Spiegel DA, Marnett LJ
(2018) Proc Natl Acad Sci U S A 115: 9228-9233
MeSH Terms: Arginine, HEK293 Cells, Histones, Humans, Lactoylglutathione Lyase, Protein Processing, Post-Translational, Pyruvaldehyde, Transcription, Genetic
Show Abstract · Added April 12, 2019
Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code. Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation. Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO). Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation. These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding. In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications. Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1. Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO. Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism.
Copyright © 2018 the Author(s). Published by PNAS.
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