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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

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

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

Front Cell Dev Biol 2020 22;8:561791. Epub 2020 Sep 22.

Laboratory of Biology and Modeling of the Cell, Ecole Normale Supérieure de Lyon, CNRS, Université Claude Bernard de Lyon, Université de Lyon, Lyon, France.

Chromatin regulators contribute to the maintenance of the germline transcriptional program. In the absence of SET-2, the homolog of the SET1/COMPASS H3 Lys4 (H3K4) methyltransferase, animals show transgenerational loss of germline identity, leading to sterility. To identify transcriptional signatures associated with progressive loss of fertility, we performed expression profiling of mutant germlines across generations. Read More

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

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

Mol Cell 2020 06 11;78(5):903-914.e4. Epub 2020 May 11.

Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address:

LSD1 (lysine specific demethylase; also known as KDM1A), the first histone demethylase discovered, regulates cell-fate determination and is overexpressed in multiple cancers. LSD1 demethylates histone H3 Lys4, an epigenetic mark for active genes, but requires the CoREST repressor to act on nucleosome substrates. To understand how an accessory subunit (CoREST) enables a chromatin enzyme (LSD1) to function on a nucleosome and not just histones, we have determined the crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome. Read More

Biochim Biophys Acta Gene Regul Mech 2020 08 8;1863(8):194578. Epub 2020 May 8.

Stem Cell Engineering, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität Dresden, Tatzberg 47, 01307 Dresden, Germany. Electronic address:

The Trithorax-related Set1 H3K4 methyltransferases are conserved from yeast to human. In yeast loss of Set1 causes pleiotropic effects but is compatible with life. In contrast, both mammalian Set1 orthologs: SETD1A and SETD1B are essential for embryonic development, however they have distinct functions. Read More

Biochim Biophys Acta Gene Regul Mech 2020 08 29;1863(8):194567. Epub 2020 Apr 29.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom. Electronic address:

The precise regulation of gene transcription is required to establish and maintain cell type-specific gene expression programs during multicellular development. In addition to transcription factors, chromatin, and its chemical modification, play a central role in regulating gene expression. In vertebrates, DNA is pervasively methylated at CG dinucleotides, a modification that is repressive to transcription. Read More

Nat Cell Biol 2020 04 30;22(4):380-388. Epub 2020 Mar 30.

DNRF Center for Chromosome Stability (CCS), Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change, whereas histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3). Read More

Onco Targets Ther 2020 14;13:381-387. Epub 2020 Jan 14.

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People's Republic of China.

Background: Mixed lineage leukemia (MLL) fusion protein alone exhibits poor histone lysine methyltransferase (HKMT) activity in catalyzing histone H3 Lys4 trimethylation (H3K4me3) in MLL-rearranged acute leukemia.

Methods: To explore the HKMT effect of another regulatory protein within the complex of proteins associated with Set 1 (COMPASS), we analyzed the H3K4me3 modification of the HOXC8 promoter under the action of ASH2L regulation. Small interfering RNA of ASH2L, chromatin immunoprecipitation, real-time-PCR (RT-PCR), and Western blotting were used to detect the expression of specific regions of the HOXC8 promoter, RBBP5, WDR5, MLL, and BRTF in two MLL-rearranged acute leukemia cell lines (RS4:11 and THP-1 cells). Read More

J Genet Genomics 2019 12 11;46(12):561-574. Epub 2019 Dec 11.

State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China. Electronic address:

Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth. However, how cells transduce nutrient availability to appropriate gene expression response via histone modifications remains largely unknown. Here, we report that glucose specifically induces histone H3K4 trimethylation (H3K4me3), an evolutionarily conserved histone covalent modification associated with active gene transcription, and that glycolytic enzymes and metabolites are required for this induction. Read More

Life Sci Alliance 2020 01 27;3(1). Epub 2019 Dec 27.

John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

Epigenetic variation reflects the impact of a dynamic environment on chromatin. However, it remains elusive how environmental factors influence epigenetic events. Here, we show that G protein-coupled receptors (GPCRs) alter H3K4 methylation via oscillatory intracellular cAMP. Read More

Nat Commun 2019 12 17;10(1):5759. Epub 2019 Dec 17.

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Read More

Cell Prolif 2020 Feb 15;53(2):e12744. Epub 2019 Dec 15.

State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.

Objectives: Mixed lineage leukaemia protein-1 (MLL1) mediates histone 3 lysine 4 (H3K4) trimethylation (me3) and plays vital roles during early embryonic development and hematopoiesis. In our previous study, we found its expression was positively correlated with embryonic myogenic ability in pigs, indicating its potential roles in mammalian muscle development. The present work aimed to explore the roles and regulation mechanisms of MLL1 in myogenesis. Read More

Cell Death Dis 2019 12 11;10(12):947. Epub 2019 Dec 11.

Jiangxi University of Science and Technology, Ganzhou, 341000, China.

Long noncoding RNAs (lncRNAs) have been demonstrated to be important regulators during the osteogenic differentiation of mesenchymal stem cells (MSCs). We analyzed the lncRNA expression profile during osteogenic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and identified a significantly downregulated lncRNA RP11-527N22.2, named osteogenic differentiation inhibitory lncRNA 1, ODIR1. Read More

J Biol Chem 2020 01 5;295(5):1271-1287. Epub 2019 Dec 5.

Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina 27709

Proteasome activity is required for diverse cellular processes, including transcriptional and epigenetic regulation. However, inhibiting proteasome activity can lead to an increase in transcriptional output that is correlated with enriched levels of trimethyl H3K4 and phosphorylated forms of RNA polymerase (Pol) II at the promoter and gene body. Here, we perform gene expression analysis and ChIP followed by sequencing (ChIP-seq) in MCF-7 breast cancer cells treated with the proteasome inhibitor MG132, and we further explore genome-wide effects of proteasome inhibition on the chromatin state and RNA Pol II transcription. Read More

Nat Commun 2019 12 5;10(1):5540. Epub 2019 Dec 5.

Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA.

Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. Read More

Nature 2019 12 4;576(7786):301-305. Epub 2019 Dec 4.

Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.

A central aspect of aging research concerns the question of when individuality in lifespan arises. Here we show that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes in motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Read More

Elife 2019 11 20;8. Epub 2019 Nov 20.

Molecular Medicine Laboratory, Rappaport Faculty of Medicine, Technion, Haifa, Israel.

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected mutations in induced pluripotent stem cells from ICF1 patients. Read More

Nucleic Acids Res 2020 01;48(1):421-431

Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

COMPlex ASsociating with SET1 (COMPASS) is a histone H3 Lys-4 methyltransferase that typically marks the promoter region of actively transcribed genes. COMPASS is a multi-subunit complex in which the catalytic unit, SET1, is required for H3K4 methylation. An important subunit known to regulate SET1 methyltransferase activity is the CxxC zinc finger protein 1 (Cfp1). Read More

Hum Mol Genet 2019 12;28(24):4089-4102

Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy.

A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Read More

Environ Toxicol 2020 Feb 5;35(2):277-291. Epub 2019 Nov 5.

College of Public Health, Zhengzhou University, Zhengzhou, China.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC-LR-induced apoptosis in testicular Sertoli cells in Sprague-Dawley (SD) rats, this study indicated that MC-LR increased the expression levels of apoptosis-related genes by raising the levels of H3K4me3. 5'-Deoxy-5'-methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC-LR. Read More

FEBS J 2020 03 23;287(6):1155-1175. Epub 2019 Oct 23.

Department of Experimental Medicine, University of Rome, Sapienza, Italy.

The 'instructive model' of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation. To provide insight into these conflicting findings, we generated DNA methylation profiles for acute myeloid leukemia samples from patients and leukemic cell lines and integrated them with publicly available ChIp-seq data, containing H3K4me3 and H3K27me3 CpG island occupation in hESC, or hematopoietic stem or progenitor cells (hHSC/MPP). Read More

Kidney Int 2019 11 1;96(5):1162-1175. Epub 2019 Aug 1.

Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan. Electronic address:

Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16 gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Read More

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

McKusick-Nathans Institute of Genetic Medicine.

Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/βGeo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Read More

New Phytol 2020 01 16;225(2):930-947. Epub 2019 Oct 16.

College of Plant Sciences, Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, China.

Histone 3 Lysine 4 (H3K4) demethylation is ubiquitous in organisms, however the roles of H3K4 demethylase JARID1(Jar1)/KDM5 in fungal development and pathogenesis remain largely unexplored. Here, we demonstrate that Jar1/KDM5 in Botrytis cinerea, the grey mould fungus, plays a crucial role in these processes. The BcJAR1 gene was deleted and its roles in fungal development and pathogenesis were investigated using approaches including genetics, molecular/cell biology, pathogenicity and transcriptomic profiling. Read More

Int J Cancer 2020 03 30;146(6):1553-1567. Epub 2019 Oct 30.

Department of Gynecology and Obstetrics, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.

Detachment of cancer cells from the primary tumor and formation of spheroids in ascites is required for implantation metastasis in epithelial ovarian cancer (EOC), but the underlying mechanism of this process has not been thoroughly elucidated. To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. Read More

Cell Rep 2019 07;28(3):698-711.e5

The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Institute of Medical Biology of the Chinese Academy of Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China. Electronic address:

Histone methylation is essential for regulating gene expression during organogenesis to maintain stem cells and execute a proper differentiation program for their descendants. Here we show that the COMPASS family histone methyltransferase co-factor ASH2L is required for maintaining neural progenitor cells (NPCs) and the production and positioning of projection neurons during neocortex development. Specifically, loss of Ash2l in NPCs results in malformation of the neocortex; the mutant neocortex has fewer neurons, which are also abnormal in composition and laminar position. Read More

Epigenetics Chromatin 2019 07 2;12(1):40. Epub 2019 Jul 2.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, International Associated Laboratory of CNRS-Fudan-HUNAU on Plant Epigenome Research, Department of Biochemistry, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Background: In animals, H3K4me2 and H3K4me3 are enriched at the transcription start site (TSS) and function as epigenetic marks that regulate gene transcription, but their functions in plants have not been fully characterized.

Results: We used chromatin immunoprecipitation sequencing to analyze the rice genome-wide changes to H3K4me1/H3K4me2/H3K4me3 following the loss of an H3K4-specific methyltransferase, SDG701. The knockdown of SDG701 resulted in a global decrease in H3K4me2/H3K4me3 levels throughout the rice genome. Read More