449 results match your criteria histone lys4

HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia.

Nat Commun 2021 03 29;12(1):1956. Epub 2021 Mar 29.

Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c). NPM1c maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c controls such gene expression patterns to promote leukemogenesis remain largely unknown. Read More

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PCA3 controls chromatin organization and p53 signal activation by regulating LAP2α-lamin A complexes.

Cancer Gene Ther 2021 Mar 23. Epub 2021 Mar 23.

Department of Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto-City, Kyoto, Japan.

Prostate cancer antigen 3 (PCA3) is a prostate cancer-specific long noncoding RNA (lncRNA). Here, we report that lncRNA PCA3 plays a role in prostate cancer progression that is mediated by nucleoplasmic lamins. PCA3 interacts with the C-terminal region of lamina-associated polypeptide (LAP) 2α. Read More

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Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains.

Nat Commun 2021 03 3;12(1):1419. Epub 2021 Mar 3.

Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. While the NCI-60 panel represents a diverse set of human cancer cell lines that has been used to screen chemical compounds, a comprehensive epigenomic atlas of these cells has been lacking. Here, we report an integrative analysis of 60 human cancer epigenomes, representing a catalog of activating and repressive histone modifications. Read More

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Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A.

ACS Chem Biol 2021 Feb 23. Epub 2021 Feb 23.

Department of Cellular and Molecular Pharmacology, University of California San Francisco, 600 16th Street, Genentech Hall, San Francisco, California 94158, United States.

PHD reader domains are chromatin binding modules often responsible for the recruitment of large protein complexes that contain histone modifying enzymes, chromatin remodelers, and DNA repair machinery. A majority of PHD domains recognize N-terminal residues of histone H3 and are sensitive to the methylation state of Lys4 in histone H3 (H3K4). Histone demethylase KDM5A, an epigenetic eraser enzyme that contains three PHD domains, is often overexpressed in various cancers, and its demethylation activity is allosterically enhanced when its PHD1 domain is bound to the H3 tail. Read More

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February 2021

A unique bipartite Polycomb signature regulates stimulus-response transcription during development.

Nat Genet 2021 03 18;53(3):379-391. Epub 2021 Feb 18.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Rapid cellular responses to environmental stimuli are fundamental for development and maturation. Immediate early genes can be transcriptionally induced within minutes in response to a variety of signals. How their induction levels are regulated and their untimely activation by spurious signals prevented during development is poorly understood. Read More

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Prenatal chlorpyrifos exposure in association with PPARγ H3K4me3 and DNA methylation levels and child development.

Environ Pollut 2021 Apr 16;274:116511. Epub 2021 Jan 16.

Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, 100, Taiwan; Department of Public Health, National Taiwan University College of Public Health, Taipei, 100, Taiwan. Electronic address:

Background: Chlorpyrifos, one of the most widely used pesticides, can penetrate the placenta and affect fetal growth and neurodevelopment. Epigenetic regulation of peroxisome proliferator-activated receptor gamma (PPARγ), such as DNA methylation and trimethylation of lysine 4 of H3 (H3K4me3), may provide a potential mechanism for how fetal growth and development are impacted by chlorpyrifos exposure. The aims of the study were to investigate whether prenatal chlorpyrifos exposure was associated with H3K4me3 and DNA methylation levels of the PPARγ gene in the placenta and the related effects on birth outcomes and neurodevelopment. Read More

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Metabolic control of DNA methylation in naive pluripotent cells.

Nat Genet 2021 02 1;53(2):215-229. Epub 2021 Feb 1.

Department of Molecular Medicine, Medical School, University of Padua, Padua, Italy.

Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF-Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Read More

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February 2021

Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations.

Nat Commun 2021 01 21;12(1):499. Epub 2021 Jan 21.

Princess Margaret Cancer Centre, Toronto, ON, M5G 1L7, Canada.

The human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Read More

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January 2021

JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications.

Science 2021 01;371(6527)

QB3 Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) cooperate to determine cell identity by epigenetic gene expression regulation. However, the mechanism of PRC2 recruitment by means of recognition of PRC1-mediated H2AK119ub1 remains poorly understood. Our PRC2 cryo-electron microscopy structure with cofactors JARID2 and AEBP2 bound to a H2AK119ub1-containing nucleosome reveals a bridge helix in EZH2 that connects the SET domain, H3 tail, and nucleosomal DNA. Read More

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January 2021

ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit.

J Biol Chem 2020 12;295(51):17738-17751

Howard Hughes Medical Institute, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Dept. of Pediatrics, Harvard Medical School, Boston, Massachusetts USA. Electronic address:

Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. Read More

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December 2020

Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression.

Nat Commun 2021 01 15;12(1):400. Epub 2021 Jan 15.

Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA.

Promoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a methylation quantification method. Read More

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January 2021

HMGB1-mediated chromatin remodeling attenuates gene expression for the protection from allergic contact dermatitis.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Department of Dermatology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. Read More

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January 2021

DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Fralin Biomedical Research Institute, Translational Biology, Medicine & Health, Virginia Polytechnic Institute and State University, Roanoke, VA 24016, USA.

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Read More

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November 2020

Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation.

Nucleic Acids Res 2020 12;48(21):12151-12168

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Histones are substrates of the SUMO (small ubiquitin-like modifier) conjugation pathway. Several reports suggest histone sumoylation affects transcription negatively, but paradoxically, our genome-wide analysis shows the modification concentrated at many active genes. We find that trans-tail regulation of histone-H2B ubiquitylation and H3K4 di-methylation potentiates subsequent histone sumoylation. Read More

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December 2020

Efficient chromatin accessibility mapping in situ by nucleosome-tethered tagmentation.

Elife 2020 11 16;9. Epub 2020 Nov 16.

Basic Sciences Division Fred Hutchinson Cancer Research Center, Seattle, United States.

Chromatin accessibility mapping is a powerful approach to identify potential regulatory elements. A popular example is ATAC-seq, whereby Tn5 transposase inserts sequencing adapters into accessible DNA ('tagmentation'). CUT&Tag is a tagmentation-based epigenomic profiling method in which antibody tethering of Tn5 to a chromatin epitope of interest profiles specific chromatin features in small samples and single cells. Read More

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November 2020

Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance.

Nucleic Acids Res 2020 11;48(20):11380-11393

Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Canada.

Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Read More

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November 2020

Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells.

Biochem Biophys Res Commun 2020 12 3;533(4):1034-1038. Epub 2020 Oct 3.

AntiCancer Inc, 7917 Ostrow St, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, 9300 Campus Point Drive #7220, La Jolla, CA, 92037-7220, USA. Electronic address:

Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction prevents cancer cells, but not normal cells from proliferation under methionine restriction (MR). Previous studies reported that MR altered the histone methylation levels in methionine-addicted cancer cells. Read More

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December 2020

Duration of cold exposure defines the rate of reactivation of a perennial FLC orthologue via H3K27me3 accumulation.

Sci Rep 2020 09 29;10(1):16056. Epub 2020 Sep 29.

Center for Ecological Research, Kyoto University, 2-509-3 Hirano, Otsu, 520-2113, Japan.

Vernalisation is the process in which long-term cold exposure makes plants competent to flower. In vernalisation of Arabidopsis thaliana, a floral repressor, AtFLC, undergoes epigenetic silencing. Although the silencing of AtFLC is maintained under warm conditions after a sufficient duration of cold, FLC orthologues are reactivated under the same conditions in perennial plants, such as A. Read More

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September 2020

Evaluating the informativeness of deep learning annotations for human complex diseases.

Nat Commun 2020 09 17;11(1):4703. Epub 2020 Sep 17.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence, but their informativeness for human complex diseases is not fully understood. Here, we evaluate genome-wide SNP annotations from two previous deep learning models, DeepSEA and Basenji, by applying stratified LD score regression to 41 diseases and traits (average N = 320K), conditioning on a broad set of coding, conserved and regulatory annotations. We aggregated annotations across all (respectively blood or brain) tissues/cell-types in meta-analyses across all (respectively 11 blood or 8 brain) traits. Read More

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September 2020

Poly(ADP-ribose) Polymerase 1 (PARP1) restrains MyoD-dependent gene expression during muscle differentiation.

Sci Rep 2020 09 15;10(1):15086. Epub 2020 Sep 15.

Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.

The myogenic factor MyoD regulates skeletal muscle differentiation by interacting with a variety of chromatin-modifying complexes. Although MyoD can induce and maintain chromatin accessibility at its target genes, its binding and trans-activation ability can be limited by some types of not fully characterized epigenetic constraints. In this work we analysed the role of PARP1 in regulating MyoD-dependent gene expression. Read More

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September 2020

Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3.

Oncogene 2020 10 2;39(41):6468-6479. Epub 2020 Sep 2.

Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Aberrations in epigenetic modulation dysregulate transcription, playing a critical role in the developmental process of tumors, including lung cancer. Aberrant levels of the histone 3 lysine-27 demethylase KDM6A have been found in cancer and are either positively or negatively associated with tumorigenesis and prognosis. However, the clinical relevance and functional role of KDM6A in lung cancer is largely unknown. Read More

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October 2020

Mechanisms Regulating Muscle Protein Synthesis in CKD.

J Am Soc Nephrol 2020 11 6;31(11):2573-2587. Epub 2020 Aug 6.

Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas.

Background: CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-B mediate the response. Read More

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November 2020

Bisphenol A-associated alterations in DNA and histone methylation affects semen quality in rare minnow Gobiocypris rarus.

Aquat Toxicol 2020 Sep 21;226:105580. Epub 2020 Jul 21.

College of Animal Science and Technology, Northwest A&F University, Yang Ling, Shaanxi, 712100, China; Toxicology and Food Contaminants Department, National Research Centre, Cairo 11435, Egypt.

Bisphenol A (BPA), a well-known estrogenic endocrine disruptor, is ubiquitously present in the environment, possessing the potential to interfere with the reproductive endocrine system in male mammals. However, there are limited studies on the reproductive toxicity in male aquatic animals associated with epigenetic modifications. In order to evaluate the potential effects of BPA on reproduction and better understand the underlying mechanism, adult male rare minnow (Gobiocypris rarus) were exposed to 15 μg L BPA over a period of 63 d. Read More

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September 2020

Transition to naïve human pluripotency mirrors pan-cancer DNA hypermethylation.

Nat Commun 2020 07 22;11(1):3671. Epub 2020 Jul 22.

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ, London, UK.

Epigenetic reprogramming is a cancer hallmark, but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We identify a dichotomy between bivalent genes that do and do not become hypermethylated, which is also mirrored in cancer. Read More

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Sharing Marks: H3K4 Methylation and H2B Ubiquitination as Features of Meiotic Recombination and Transcription.

Int J Mol Sci 2020 Jun 25;21(12). Epub 2020 Jun 25.

Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia (CSIC), Jaume Roig, 11, 46010 Valencia, Spain.

Meiosis is a specialized cell division that gives raise to four haploid gametes from a single diploid cell. During meiosis, homologous recombination is crucial to ensure genetic diversity and guarantee accurate chromosome segregation. Both the formation of programmed meiotic DNA double-strand breaks (DSBs) and their repair using homologous chromosomes are essential and highly regulated pathways. Read More

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Genome-wide analysis of H3K4me3 and H3K27me3 modifications due to Lr28 for leaf rust resistance in bread wheat (Triticum aestivum).

Plant Mol Biol 2020 Sep 5;104(1-2):113-136. Epub 2020 Jul 5.

Department of Genetics and Plant Breeding, Chaudhary Charan Singh University, Meerut, U.P., 250004, India.

Key Message: Present study revealed a complex relationship among histone H3 methylation (examined using H3K4/K27me3 marks), cytosine DNA methylation and differential gene expression during Lr28 mediated leaf rust resistance in wheat. During the present study, genome-wide histone modifications were examined in a pair of near isogenic lines (NILs) (with and without Lr28 in the background of cv. HD2329). Read More

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September 2020

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.

Nat Commun 2020 07 3;11(1):3339. Epub 2020 Jul 3.

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. Read More

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Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1.

PLoS One 2020 23;15(6):e0234913. Epub 2020 Jun 23.

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States of America.

The transcriptional regulatory machinery in mitochondrial bioenergetics is complex and is still not completely understood. We previously demonstrated that the histone methyltransferase Smyd1 regulates mitochondrial energetics. Here, we identified Perm1 (PPARGC-1 and ESRR-induced regulator, muscle specific 1) as a downstream target of Smyd1 through RNA-seq. Read More

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September 2020

Terbium-to-quantum dot Förster resonance energy transfer for homogeneous and sensitive detection of histone methyltransferase activity.

Nanoscale 2020 Jul;12(25):13719-13730

Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France and nanoFRET.com, Laboratoire COBRA (Chimie Organique, Bioorganique, Réactivité et Analyse), Université de Rouen Normandie, CNRS, INSA, 76821 Mont-Saint-Aignan, France.

The development of rapid, simple, and versatile biosensors for monitoring the activity of histone modifying enzymes (HMEs) is needed for the improvement of diagnostic assays, screening of HME inhibitors, and a better understanding of HME kinetics in different environments. Nanoparticles can play an important role in this regard by improving or complementing currently available enzyme detection technologies. Here, we present the development and application of a homogeneous methyltransferase (SET7/9) assay based on time-gated Förster resonance energy transfer (TG-FRET) between terbium complexes (Tb) and luminescent semiconductor quantum dots (QDs). Read More

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Epigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment.

Nat Struct Mol Biol 2020 08 22;27(8):696-705. Epub 2020 Jun 22.

Epigenetics Programme, Babraham Institute, Cambridge, UK.

How the epigenetic landscape is established in development is still being elucidated. Here, we uncover developmental pluripotency associated 2 and 4 (DPPA2/4) as epigenetic priming factors that establish a permissive epigenetic landscape at a subset of developmentally important bivalent promoters characterized by low expression and poised RNA-polymerase. Differentiation assays reveal that Dppa2/4 double knockout mouse embryonic stem cells fail to exit pluripotency and differentiate efficiently. Read More

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