303 results match your criteria h3k4 demonstrate


H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation.

Arterioscler Thromb Vasc Biol 2021 Apr 8:ATVBAHA121314689. Epub 2021 Apr 8.

State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau (D.Y., Y.Z.Z.).

Objective: Smyd3 (SET and MYND domain-containing protein 3) is an H3K4 (histone H3 lysine 4) dimethyltransferase and trimethyltransferase that activates the transcription of oncogenes and cell cycle genes in human cancer cells. We discovered its overexpression in proliferative vascular smooth muscle cells (VSMCs). However, whether Smyd3 plays a role in vascular remodeling remains unanswered. Read More

View Article and Full-Text PDF

A functional LSD1 coregulator screen reveals a novel transcriptional regulatory cascade connecting R-loop homeostasis with epigenetic regulation.

Nucleic Acids Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany.

The lysine specific demethylase 1 (LSD1) plays a pivotal role in cellular differentiation by regulating the expression of key developmental genes in concert with different coregulatory proteins. This process is impaired in different cancer types and incompletely understood. To comprehensively identify functional coregulators of LSD1, we established a novel tractable fluorescent reporter system to monitor LSD1 activity in living cells. Read More

View Article and Full-Text PDF

An enzyme-based biosensor for monitoring and engineering protein stability in vivo.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing, East China University of Science and Technology, Shanghai 200237, China

Protein stability affects the physiological functions of proteins and is also a desirable trait in many protein engineering tasks, yet improving protein stability is challenging because of limitations in methods for directly monitoring protein stability in cells. Here, we report an in vivo stability biosensor wherein a protein of interest (POI) is inserted into a microbial enzyme (CysG) that catalyzes the formation of endogenous fluorescent compounds, thereby coupling POI stability to simple fluorescence readouts. We demonstrate the utility of the biosensor in directed evolution to obtain stabilized, less aggregation-prone variants of two POIs (including nonamyloidogenic variants of human islet amyloid polypeptide). Read More

View Article and Full-Text PDF

Hsa_circ_001659 serves as a novel diagnostic and prognostic biomarker for colorectal cancer.

Biochem Biophys Res Commun 2021 Apr 13;551:100-106. Epub 2021 Mar 13.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200240, China. Electronic address:

Colorectal cancer (CRC) is prevalent worldwide and novel diagnostic and prognostic biomarkers are needed to improve precision medicine. Circular RNAs (circRNAs) are currently being considered as emerging tumor biomarkers. Herein, we aimed to explore the possible clinical application of circRNAs in the early diagnosis and prognostic prediction of CRC. Read More

View Article and Full-Text PDF

The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers.

Cell Rep 2021 Feb;34(6):108742

Institute for Diabetes and Obesity (IDO) & Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), 85764 Neuherberg (Munich), Germany; Metabolic Programming, School of Life Sciences Weihenstephan, ZIEL - Institute for Food & Health, Technische Universitaet Muenchen (TUM), 85354 Freising, Germany; Metabolic Biochemistry and Genetics, Gene Center, Ludwig-Maximilians-Universitaet LMU, 81377 Munich, Germany. Electronic address:

Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling gene expression in numerous cell types. Here, we characterize GR's protein interactome and find the SETD1A (SET domain containing 1A)/COMPASS (complex of proteins associated with Set1) histone H3 lysine 4 (H3K4) methyltransferase complex highly enriched in activated mouse macrophages. Read More

View Article and Full-Text PDF
February 2021

Molecular mechanics and dynamic simulations of well-known Kabuki syndrome-associated KDM6A variants reveal putative mechanisms of dysfunction.

Orphanet J Rare Dis 2021 Feb 5;16(1):66. Epub 2021 Feb 5.

Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Kabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity. The syndrome is named for a common phenotype of faces resembling stage makeup used in a Japanese traditional theatrical art named kabuki. The most frequent cause of this syndrome is mutations in the H3K4 family of histone methyltransferases while a smaller percentage results from genetic alterations affecting the histone demethylase, KDM6A. Read More

View Article and Full-Text PDF
February 2021

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

Sci Rep 2021 Jan 26;11(1):2203. Epub 2021 Jan 26.

Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.

S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. Read More

View Article and Full-Text PDF
January 2021

EBF1 drives hallmark B cell gene expression by enabling the interaction of PAX5 with the MLL H3K4 methyltransferase complex.

Sci Rep 2021 Jan 15;11(1):1537. Epub 2021 Jan 15.

Atlantic Cancer Research Institute, Pavillon Hôtel-Dieu, 35 Providence Street, Moncton, NB, E1C 8X3, Canada.

PAX5 and EBF1 work synergistically to regulate genes that are involved in B lymphocyte differentiation. We used the KIS-1 diffuse large B cell lymphoma cell line, which is reported to have elevated levels of PAX5 expression, to investigate the mechanism of EBF1- and PAX5-regulated gene expression. We demonstrate the lack of expression of hallmark B cell genes, including CD19, CD79b, and EBF1, in the KIS-1 cell line. Read More

View Article and Full-Text PDF
January 2021

HOXA5 Expression Is Elevated in Breast Cancer and Is Transcriptionally Regulated by Estradiol.

Front Genet 2020 15;11:592436. Epub 2020 Dec 15.

Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, United States.

HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. Read More

View Article and Full-Text PDF
December 2020

The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.

Nat Commun 2020 12 21;11(1):6422. Epub 2020 Dec 21.

Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125, Berlin, Germany.

Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5 stem cells and human colon carcinomas with increased nuclear β-catenin. Read More

View Article and Full-Text PDF
December 2020

Aberrant Activity of Histone-Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis.

Int J Mol Sci 2020 Dec 8;21(24). Epub 2020 Dec 8.

Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614 Poznań, Poland.

KMT2 (histone-lysine N-methyltransferase subclass 2) complexes methylate lysine 4 on the histone H3 tail at gene promoters and gene enhancers and, thus, control the process of gene transcription. These complexes not only play an essential role in normal development but have also been described as involved in the aberrant growth of tissues. KMT2 mutations resulting from the rearrangements of the KMT2A (MLL1) gene at 11q23 are associated with pediatric mixed-lineage leukemias, and recent studies demonstrate that KMT2 genes are frequently mutated in many types of human cancers. Read More

View Article and Full-Text PDF
December 2020

Histone H3K4 methyltransferases SDG25 and ATX1 maintain heat-stress gene expression during recovery in Arabidopsis.

Plant J 2021 Mar 4;105(5):1326-1338. Epub 2021 Jan 4.

State Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, 310027, China.

Plants have short-term stress memory that enables them to maintain the expression state of a substantial subset of heat-inducible genes during stress recovery after heat stress. Little is known about the molecular mechanisms controlling stress-responsive gene expression at the recovery stage in plants, however. In this article, we demonstrate that histone H3K4 methyltransferases SDG25 and ATX1 are required for heat-stress tolerance in Arabidopsis. Read More

View Article and Full-Text PDF

MLL5, a histone modifying enzyme, regulates androgen receptor activity in prostate cancer cells by recruiting co-regulators, HCF1 and SET1.

BMB Rep 2020 Dec;53(12):634-639

Department of Urology, Seoul National University Hospital, Seoul 03080, Korea; Department of Urology, Seoul National University College of Medicine, Seoul 03080, Korea.

In prostate cancer, the androgen receptor (AR) transcription factor is a major regulator of cell proliferation and metastasis. To identify new AR regulators, we focused on Mixed lineage leukemia 5 (MLL5), a histone-regulating enzyme, because significantly higher MLL5 expression was detected in prostate cancer tissues than in matching normal tissues. When we expressed shRNAs targeting MLL5 gene in prostate cancer cell line, the growth rate and AR activity were reduced compared to those in control cells, and migration ability of the knockdown cells was reduced significantly. Read More

View Article and Full-Text PDF
December 2020

The Polycomb group methyltransferase StE(z)2 and deposition of H3K27me3 and H3K4me3 regulate the expression of tuberization genes in potato.

J Exp Bot 2021 Feb;72(2):426-444

Biology Division, Dr. Homi Bhabha Road, Indian Institute of Science Education and Research (IISER) Pune, Maharashtra - 411008, India.

Polycomb repressive complex (PRC) group proteins regulate various developmental processes in plants by repressing target genes via H3K27 trimethylation, and they function antagonistically with H3K4 trimethylation mediated by Trithorax group proteins. Tuberization in potato has been widely studied, but the role of histone modifications in this process is unknown. Recently, we showed that overexpression of StMSI1, a PRC2 member, alters the expression of tuberization genes in potato. Read More

View Article and Full-Text PDF
February 2021

H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage.

Nat Struct Mol Biol 2020 12 12;27(12):1165-1177. Epub 2020 Oct 12.

Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany.

DNA damage causes cancer, impairs development and accelerates aging. Transcription-blocking lesions and transcription-coupled repair defects lead to developmental failure and premature aging in humans. Following DNA repair, homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Read More

View Article and Full-Text PDF
December 2020

A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals.

Genes Dev 2020 Oct 8. Epub 2020 Oct 8.

Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60611, USA.

Catalytic-inactivating mutations within the enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Read More

View Article and Full-Text PDF
October 2020

Transient Changes of Metabolism at the Pronuclear Stage in Mice Influences Skeletal Muscle Phenotype in Adulthood.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

DMEM, Univ. Montpellier, INRAE, 34060 Montpellier, France.

Skeletal muscle has a remarkable plasticity, and its phenotype is strongly influenced by hormones, transcription factors, and physical activity. However, whether skeletal phenotype can be oriented or not during early embryonic stages has never been investigated. Here, we report that pyruvate as the only source of carbohydrate in the culture medium of mouse one cell stage embryo influenced the establishment of the muscular phenotype in adulthood. Read More

View Article and Full-Text PDF
September 2020

The conserved elongation factor Spn1 is required for normal transcription, histone modifications, and splicing in Saccharomyces cerevisiae.

Nucleic Acids Res 2020 10;48(18):10241-10258

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Spn1/Iws1 is a conserved protein involved in transcription and chromatin dynamics, yet its general in vivo requirement for these functions is unknown. Using a Spn1 depletion system in Saccharomyces cerevisiae, we demonstrate that Spn1 broadly influences several aspects of gene expression on a genome-wide scale. We show that Spn1 is globally required for normal mRNA levels and for normal splicing of ribosomal protein transcripts. Read More

View Article and Full-Text PDF
October 2020

CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade.

Cancer Discov 2020 Dec 4;10(12):1912-1933. Epub 2020 Sep 4.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.

Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. Read More

View Article and Full-Text PDF
December 2020

Long Noncoding RNA AW112010 Promotes the Differentiation of Inflammatory T Cells by Suppressing IL-10 Expression through Histone Demethylation.

J Immunol 2020 08 20;205(4):987-993. Epub 2020 Jul 20.

Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209

Long noncoding RNAs (lncRNAs) have been demonstrated to play important regulatory roles in gene expression, from histone modification to protein stability. However, the functions of most identified lncRNAs are not known. In this study, we investigated the role of an lncRNA called AW112010. Read More

View Article and Full-Text PDF

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly correlated with the survival rate of patients with prostate cancer. Read More

View Article and Full-Text PDF

-associated neurodevelopmental disorder.

J Med Genet 2021 Mar 16;58(3):196-204. Epub 2020 Jun 16.

Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability. Read More

View Article and Full-Text PDF

Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.

Nat Genet 2020 06 11;52(6):615-625. Epub 2020 May 11.

Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. Read More

View Article and Full-Text PDF

Darolutamide antagonizes androgen signaling by blocking enhancer and super-enhancer activation.

Mol Oncol 2020 09 5;14(9):2022-2039. Epub 2020 Jun 5.

Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany.

Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early-stage PCa and late-stage PCa are dependent on androgen signaling, and inhibitors of the androgen receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR-bound cistrome in two PCa cell models. Read More

View Article and Full-Text PDF
September 2020

Melatonin ameliorates murine fetal oocyte meiotic dysfunction in F1 and F2 offspring caused by nicotine exposure during pregnancy.

Environ Pollut 2020 Aug 14;263(Pt A):114519. Epub 2020 Apr 14.

College of Life Sciences, Institute of Reproductive Sciences, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

Although there is abundant evidence to demonstrate that maternal smoking during pregnancy will harm the health of future generations, the impact of nicotine use by pregnant woman upon the oogenesis and folliculogenesis of female offspring has not been as widely scrutinized. Here we focus on the effects of nicotine on the meiotic progression of fetal oocytes. The data indicated that in pregnant mice treated with nicotine, intracellular ROS increased in follicles within the fetal ovary. Read More

View Article and Full-Text PDF

Subverts Host Immune Response by Epigenetic Reprogramming of Macrophage M(Lipopolysaccharides + IFN-γ)/M(IL-10) Polarization.

J Immunol 2020 05 10;204(10):2762-2778. Epub 2020 Apr 10.

Division of Molecular Parasitology and Immunology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, India; and Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India

Reciprocal changes in histone lysine methylation/demethylation of M(LPS + IFN-γ)/M(IL-10) genes is one of the factors that direct macrophage polarization and contribute to host defense/susceptibility toward infection. Although, histone lysine methyltransferases and lysine demethylases orchestrate these events, their role remains elusive in visceral leishmaniasis, a disease associated with macrophage M(IL-10) polarization. In this study, we observed that induced the expression of histone lysine methyltransferases Ash1l, Smyd2, and Ezh2 and histone lysine demethylases Kdm5b and Kdm6b in J774 macrophages and BALB/c mice. Read More

View Article and Full-Text PDF

GSK343, an inhibitor of EZH2, mitigates fibrosis and inflammation mediated by HIF-1α in human peritoneal mesothelial cells treated with high glucose.

Eur J Pharmacol 2020 Aug 25;880:173076. Epub 2020 Mar 25.

Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. Electronic address:

Inflammation and fibrosis in peritoneal mesothelial cells caused by long-term peritoneal dialysis (PD) are the main reasons why patients withdraw from peritoneal dialysis treatment. However, the related mechanism is still unclear. In the current study, we revealed that the expression of EZH2 was positively related to EMT and fibrosis in an in vitro model using human peritoneal mesothelial cells (HPMCs) stimulated with high glucose. Read More

View Article and Full-Text PDF

Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, lead to noncompaction cardiomyopathy in mice.

Biochem Biophys Res Commun 2020 Feb 17. Epub 2020 Feb 17.

Laboratory of Stem Cell Biology, Department of Biosciences, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan. Electronic address:

Mammalian X and Y chromosomes evolved from a pair of autosomes. Although most ancestral genes have been lost from the Y chromosome, a small number of ancestral X-Y gene pairs are still present on the sex chromosomes. The KDM5C and KDM5D genes, which encode H3K4 histone demethylases, are a surviving ancestral gene pair located on the X and Y chromosomes, respectively. Read More

View Article and Full-Text PDF
February 2020

Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A.

Biochemistry 2020 02 30;59(5):647-651. Epub 2020 Jan 30.

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

Human lysine demethylase KDM5A is a chromatin-modifying enzyme associated with transcriptional regulation, because of its ability to catalyze removal of methyl groups from methylated lysine 4 of histone H3 (H3K4me3). Amplification of KDM5A is observed in many cancers, including breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer, and gastric cancer. In this study, we employed alanine scanning mutagenesis to investigate substrate recognition of KDM5A and identify the H3 tail residues necessary for KDM5A-catalyzed demethylation. Read More

View Article and Full-Text PDF
February 2020

Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

A terminally differentiated cellular phenotype is thought to be maintained, at least in part, by both active and repressive histone marks. However, it is unclear whether regenerating cells after injury need to replicate such epigenetic marks to recover. To test whether renal epithelial cell regeneration is dependent on histone H3K4 methylation, we generated a mouse model that deleted the Paxip1 gene in mature renal proximal tubules. Read More

View Article and Full-Text PDF
February 2020