• epigenetic
• gene silencing
• heterochromatin
• histone methylation

• Histones/metabolism
• Heterochromatin/genetics
• Heterochromatin/metabolism
• Schizosaccharomyces pombe Proteins/metabolism
• Chromatin Assembly and Disassembly
• Schizosaccharomyces/genetics
• Schizosaccharomyces/metabolism
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Epigenesis, Genetic

• ZIA BC011208 Intramural NIH HHS
• HHS | NIH | National Cancer Institute (NCI)

• mitochondrial genes
• neo-functionalization
• respiratory metabolism
• transcriptional coregulators

• Consejo Nacional de Ciencia y Tecnología
• Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

• DNA methylation
• carcinogenesis
• epigenetic therapy
• tumorigenesis

• Humans
• Histones/genetics
• Histones/metabolism
• Chromatin/genetics
• Nucleosomes/genetics
• DNA Methylation
• Neoplasms/genetics
• Neoplasms/therapy
• DNA/chemistry
• DNA/metabolism
• Epigenesis, Genetic

• cancer
• clusterin
• cornea
• eye
• gene expression
• wound healing

• Animals
• Humans
• Male
• Cell Communication
• Clusterin/genetics
• Eye Diseases/genetics
• Neoplasms/genetics
• Semen
• Sheep
• Wound Healing

• FDN-143213 CIHR

• epigenetic
• heterochromatin
• histone methylation
• inheritance
• read-write
• silencing

• Histones/genetics
• Histones/metabolism
• Heterochromatin/genetics
• Heterochromatin/metabolism
• Schizosaccharomyces pombe Proteins/genetics
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Schizosaccharomyces/genetics
• Epigenesis, Genetic

• Z01 BC010523 Intramural NIH HHS
• Z99 CA999999 Intramural NIH HHS
• ZIA BC010523 Intramural NIH HHS
• ZIA BC011208 Intramural NIH HHS

• Bladder cancer
• Circular RNAs
• Long non-coding RNAs
• microRNAs

Epigenetic modifications are inherited differences in cellular phenotypes, such as cell gene expression alterations, that occur during somatic cell divisions (also, in rare circumstances, in germ line transmission), but no alterations to the DNA sequence are involved. Histone alterations, polycomb/trithorax associated proteins, short non-coding or short RNAs, long non—coding RNAs (lncRNAs), & DNA methylation are just a few biological processes involved in epigenetic events. These various modifications are intricately linked. The transcriptional potential of genes is closely conditioned by epigenetic control, which is crucial in normal growth and development. Epigenetic mechanisms transmit genomic adaptation to an environment, resulting in a specific phenotype. The purpose of this systematic review is to glance at the roles of Estrogen signalling, polycomb/trithorax associated proteins, DNA methylation in breast cancer progression, as well as epigenetic mechanisms in breast cancer therapy, with an emphasis on functionality, regulatory factors, therapeutic value, and future challenges.

• Deutsche Forschungsgemeinschaft

• chromatin regulation
• chromosomes
• epigenetics
• gene expression
• human
• insulators
• mammalian synthetic biology
• spatial-temporal dynamics

• Animals
• Chromatin/genetics
• Gene Expression Regulation
• Gene Silencing
• Heterochromatin/genetics
• Insulator Elements
• Mammals/genetics

• R35 GM128947 NIGMS NIH HHS
• T32 GM007365 NIGMS NIH HHS
• T32 GM008412 NIGMS NIH HHS
• T32 GM113854 NIGMS NIH HHS
• Burroughs Wellcome Fund
• NIH Office of the Director
• Japan Society for the Promotion of Science
• National Science Foundation
• Stanford University

• METTL3
• m6A
• miR-182
• prostate cancer

• Cancer
• Drug discovery
• METTL14
• RNA modification
• m6A

• Adenine/analogs & derivatives
• Adenine/metabolism
• Animals
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Methylation
• Methyltransferases/analysis
• Methyltransferases/genetics
• Methyltransferases/metabolism
• Neoplasms/diagnosis
• Neoplasms/genetics
• Neoplasms/metabolism
• Prognosis
• RNA/genetics
• RNA/metabolism

• National Natural Science Foundation of China
• Postdoctoral Research Foundation of China
• China Postdoctoral Science Foundation
• Guangzhou Science and Technology Project

Understanding the molecular basis of sex differences in neural response to acute hypoxic insult has profound implications for the effective prevention and treatment of ischemic stroke. Global hypoxic-ischemic induced neural damage has been studied recently under well-controlled, non-invasive, reproducible conditions using a zebrafish model. Our earlier report on sex difference in global acute hypoxia-induced neural damage and recovery in zebrafish prompted us to conduct a comprehensive study on the mechanisms underlying the recovery. An omics approach for studying quantitative changes in brain proteome upon hypoxia insult following recovery was undertaken using iTRAQ-based LC-MS/MS approach. The results shed light on the altered expression of many regulatory proteins in the zebrafish brain upon acute hypoxia following recovery. The sex difference in differentially expressed proteins along with the proteins expressed in a uniform direction in both the sexes was studied. Core expression analysis by Ingenuity Pathway Analysis (IPA) showed a distinct sex difference in the disease function heatmap. Most of the upstream regulators obtained through IPA were validated at the transcriptional level. Translational upregulation of H3K9me3 in males led us to elucidate the mechanism of recovery by confirming transcriptional targets through ChIP-qPCR. The upregulation of H3K9me3 level in males at 4 h post-hypoxia appears to affect the early neurogenic markers nestin, klf4, and sox2, which might explain the late recovery in males, compared to females. Acute hypoxia-induced sex-specific comparison of brain proteome led us to reveal many differentially expressed proteins, which can be further studied for the development of novel targets for better therapeutic strategy.

Osteoporosis is a prevalent bone disease of the aging population, which is characterized by a decrease in bone mass because of the imbalance of bone metabolism. Although the prevention and treatment of osteoporosis have been explored by different researchers, the mechanisms underlying osteoporosis are not clear exactly. N6 methyladenosine (m6A) is a methylated adenosine nucleotide, which functions through its interaction with the proteins called “writers,” “readers” and “erasers.” The epigenetic regulation of m6A has been demonstrated to affect mRNA processing, nuclear export, translation, and splicing. At the cellular level, m6A modification has been known to affect cell proliferation, differentiation, and apoptosis of bone-related cells, such as bone marrow mesenchymal stem cells (BMSC), osteoblasts, and osteoclasts by regulating the expression of ALP, Runx2, Osterix, VEGF, and other related genes. Furthermore, PTH/Pth1r, PI3K‐Akt, Wnt/β‐Catenin, and other signaling pathways, which play important roles in the regulation of bone homeostasis, are also regulated by m6A. Thus, m6A modification may provide a new approach for osteoporosis treatment. The key roles of m6A modification in the regulation of bone health and osteoporosis are reviewed here in this article.

• bone marrow mesenchymal stem cells
• bone remodeling
• m6A methylation
• osteoporosis
• signaling pathways

• Butyrate sodium
• Dietary supplement
• Gut inflammatory diseases
• Histone deacetylase inhibitor
• Short chain fatty acids

• Inflammation
• Lipopolysaccharide
• Lysine-specific demethylase 1
• Mastitis
• NF-κB

• Animals
• Anti-Inflammatory Agents/pharmacology
• Cells, Cultured
• Cytokines/genetics
• Cytokines/metabolism
• Disease Models, Animal
• Enzyme Inhibitors/pharmacology
• Epigenesis, Genetic/drug effects
• Epithelial Cells/drug effects
• Epithelial Cells/enzymology
• Epithelial Cells/pathology
• Female
• Histone Demethylases/antagonists & inhibitors
• Histone Demethylases/genetics
• Histone Demethylases/metabolism
• Humans
• Inflammation Mediators/metabolism
• Lipopolysaccharides
• Mammary Glands, Human/drug effects
• Mammary Glands, Human/enzymology
• Mammary Glands, Human/pathology
• Mastitis/chemically induced
• Mastitis/enzymology
• Mastitis/genetics
• Mastitis/prevention & control
• Mice, Inbred BALB C
• NF-kappa B/metabolism
• Mice

• CPF
• Mmi1
• RNA polymerase II
• YTH
• facultative
• gene silencing
• heterochromatin
• histone methylation
• pre-mRNA processing
• transcription termination

• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Chromatin Assembly and Disassembly/genetics
• Exoribonucleases/genetics
• Exoribonucleases/metabolism
• Gene Expression Regulation, Fungal
• Gene Silencing
• Heterochromatin/metabolism
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Meiosis/genetics
• Phosphoprotein Phosphatases/genetics
• Phosphoprotein Phosphatases/metabolism
• RNA Interference
• RNA Polymerase II/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Schizosaccharomyces/genetics
• Schizosaccharomyces/metabolism
• Schizosaccharomyces pombe Proteins/genetics
• Schizosaccharomyces pombe Proteins/metabolism
• Transcription Termination, Genetic
• mRNA Cleavage and Polyadenylation Factors/genetics
• mRNA Cleavage and Polyadenylation Factors/metabolism

• Z01 BC010523 Intramural NIH HHS
• ZIA BC011208 Intramural NIH HHS
• ZIA BC010523 Intramural NIH HHS
• Z99 CA999999 Intramural NIH HHS
• FI2 GM123947 NIGMS NIH HHS

• R-loop
• common fragile sites
• g4 quadruplex
• genome stability
• replication fork

• H3K4 methylation
• Set1/COMPASS
• facultative heterochromatin
• gene orientation
• heterochromatin spreading

• Acetylation
• Catalysis
• Cell Cycle Proteins/metabolism
• Enzyme Activation
• Gene Expression Regulation, Fungal
• Gene Silencing
• Heterochromatin/metabolism
• Histone-Lysine N-Methyltransferase/metabolism
• Histones/metabolism
• Nucleosomes/metabolism
• Schizosaccharomyces/enzymology
• Schizosaccharomyces/genetics
• Schizosaccharomyces pombe Proteins/metabolism
• Transcription Factors/metabolism

• T32 GM007810 NIGMS NIH HHS
• P30 DK063720 NIDDK NIH HHS
• S10 OD021822 NIH HHS
• R35 GM141888 NIGMS NIH HHS
• DP2 GM123484 NIGMS NIH HHS
• National Institutes of Health
• Sandler Foundation
• ARCS Foundation Scholarship
• NIH
• Diabetes Research Center

• Chromatin
• DNA methylation
• Epigenetics
• Histone
• Lead (Pb)
• miRNA; Toxicity

• Alzheimer Disease
• Attention Deficit Disorder with Hyperactivity
• DNA Methylation
• Environmental Exposure/analysis
• Environmental Pollutants
• Epigenesis, Genetic
• Histone Code
• Humans
• Lead
• MicroRNAs
• Protein Processing, Post-Translational

METTL3 is known to be involved in all stages in the life cycle of RNA. It affects the tumor formation by the regulation the m6A modification in the mRNAs of critical oncogenes or tumor suppressors. In bladder cancer, METTL3 could promote the bladder cancer progression via AFF4/NF-κB/MYC signaling network by an m6A dependent manner. Recently, METTL3 was also found to affect the m6A modification in non-coding RNAs including miRNAs, lincRNAs and circRNAs. However, whether this mechanism is related to the proliferation of tumors induced by METTL3 is not reported yet.

Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of METTL3 in bladder cancer. The survival analysis was adopted to explore the association between METTL3 expression and the prognosis of bladder cancer. Bladder cancer cells were stably transfected with lentivirus and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of METTL3 in bladder cancer. RNA immunoprecipitation (RIP), co-immunoprecipitations and RNA m6A dot blot assays were conducted to confirm that METTL3 interacted with the microprocessor protein DGCR8 and modulated the pri-miR221/222 process in an m6A-dependent manner. Luciferase reporter assay was employed to identify the direct binding sites of miR221/222 with PTEN. Colony formation assay and CCK8 assays were conducted to confirm the function of miR-221/222 in METTL3-induced cell growth in bladder cancer.

We confirmed the oncogenic role of METTL3 in bladder cancer by accelerating the maturation of pri-miR221/222, resulting in the reduction of PTEN, which ultimately leads to the proliferation of bladder cancer. Moreover, we found that METTL3 was significantly increased in bladder cancer and correlated with poor prognosis of bladder cancer patients.

Our findings suggested that METTL3 may have an oncogenic role in bladder cancer through interacting with the microprocessor protein DGCR8 and positively modulating the pri-miR221/222 process in an m6A-dependent manner. To our knowledge, this is the first comprehensive study that METTL3 affected the tumor formation by the regulation the m6A modification in non-coding RNAs, which might provide fresh insights into bladder cancer therapy.

The online version of this article (10.1186/s12943-019-1036-9) contains supplementary material, which is available to authorized users.

• Bladder cancer
• METTL3
• PTEN
• m6A
• miR221/222

First identified in 1974, m⁶A RNA methylation, which serves as a predominant internal modification of RNA in higher eukaryotes, has gained prodigious interest in recent years. Modifications of m⁶A are dynamic and reversible in mammalian cells, which have been proposed as another layer of epigenetic regulation similar to DNA and histone modifications. m⁶A RNA methylation is involved in all stages in the life cycle of RNA, ranging from RNA processing, through nuclear export, translation modulation to RNA degradation, which suggests its potential of influencing a plurality of aspects of RNA metabolism. All of the recent studies have pointed to a complicated regulation network of m⁶A modification in different tissues, cell lines, and space–time models. m⁶A methylation has been found to have an impact on tumor initiation and progression through various mechanisms. Furthermore, m⁶A RNA methylation has provided new opportunities for early stage diagnosis and treatment of cancers.

Herein, we review the chemical basis of m⁶A RNA methylation, its multiple functions and potential significance in cancer.

• Cancer
• Mechanism
• RNA methylation
• m6A

• DNA methylation
• brain-derived neurotrophic factor
• histone modification
• mood disorders
• negative stressors

• amino acid metabolism
• aminotransferases
• expression regulation
• functional diversification
• paralogous genes

• Chromatin structure
• DNA packaging
• Gene expression
• Genomic organization

• Fft3
• SMARCAD1
• epigenetic inheritance
• heterochromatin
• nucleosome turnover
• replication

α-Synuclein (αS) is a protein linked to Parkinson’s disease (PD) and related neurodegenerative disorders. It is mostly localized within synapses, but αS has also been suggested to play a role in the nucleus. We used transgenic Drosophila and inducible SH-SY5Y neuroblastoma cells to investigate the effects of αS on chromatin with a particular focus on histone modifications. Overexpression of αS in male flies as well as in retinoic acid pre-treated neuroblastoma cells led to an elevation of histone H3K9 methylations, mostly mono- (H3K9me1) and di- (H3K9me2). The transient increase of H3K9 methylation in αS-induced SH-SY5Y cells was preceded by mRNA induction of the euchromatic histone lysine N-methyltransferase 2 (EHMT2). EHMT2 and H3K9me2 can function within the REST complex. Chromatin immunoprecipitation (ChIP) analyses of selected candidate, REST regulated genes showed significantly increased H3K9me2 promoter occupancy of genes encoding the L1CAM cell adhesion molecule and the synaptosomal-associated protein SNAP25, whose reduced expression levels were confirmed by RT-qPCR in αS induced cells. Treatment with EHMT inhibitor UNC0638 restored the mRNA levels of L1CAM and SNAP25. Thus, αS overexpression enhances H3K9 methylations via ΕΗΜΤ2 resulting in elevated H3K9me2 at the SNAP25 promoter, possibly affecting SNARE complex assembly and hence synaptic vesicle fusion events regulated by αS.

In C. elegans, in order to equalize gene expression between the sexes and balance X and autosomal expression, two steps are believed to be required. First, an unknown mechanism is hypothesized to upregulate the X chromosome in both sexes. This mechanism balances the X to autosomal expression in males, but creates X overexpression in hermaphrodites. Therefore, to restore the balance, hermaphrodites downregulate gene expression twofold on both X chromosomes. While many studies have focused on X chromosome downregulation, the mechanism of X upregulation is not known.

To gain more insight into X upregulation, we studied the effects of chromatin condensation and histone acetylation on gene expression levels in male C. elegans. We have found that the H4K16 histone acetyltransferase MYS-1/Tip60 mediates dramatic decondensation of the male X chromosome as measured by FISH. However, RNA-seq analysis revealed that MYS-1 contributes only slightly to upregulation of gene expression on the X chromosome. These results suggest that the level of chromosome decondensation does not necessarily correlate with the degree of gene expression change in vivo. Furthermore, the X chromosome is more sensitive to MYS-1-mediated decondensation than the autosomes, despite similar levels of H4K16ac on all chromosomes, as measured by ChIP-seq. H4K16ac levels weakly correlate with gene expression levels on both the X and the autosomes, but highly expressed genes on the X chromosome do not contain exceptionally high levels of H4K16ac.

These results indicate that H4K16ac and chromosome decondensation influence regulation of the male X chromosome; however, they do not fully account for the high levels of gene expression observed on the X chromosomes.

The online version of this article (doi:10.1186/s13072-016-0097-x) contains supplementary material, which is available to authorized users.

• Caenorhabditis elegans
• Chromatin
• Chromosome territories
• Dosage compensation
• Epigenetics
• Gene expression
• Histone acetylation

• Brugada syndrome
• Notch receptors Purkinje cells
• action potential
• cardiomyopathies
• cellular reprogramming
• electrophysiology

Although ICP4 is the only essential transcription activator of herpes simplex virus 1 (HSV-1), its mechanisms of action are still only partially understood. We and others propose a model in which HSV-1 genomes are chromatinized as a cellular defense to inhibit HSV-1 transcription. To counteract silencing, HSV-1 would have evolved proteins that prevent or destabilize chromatinization to activate transcription. These proteins should act as HSV-1 transcription activators. We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1. We now show that whereas HSV-1 mutants encoding no functional ICP0 or VP16 partially enhanced histone dynamics, mutants encoding no functional ICP4 did so only minimally. Transient expression of ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or HSV-1 DNA. The dynamics of H3.1 were increased in cells expressing ICP4 to a greater extent than those of H3.3. The dynamics of H2B were increased in cells expressing ICP4, whereas those of canonical H2A were not. ICP4 preferentially targets silencing H3.1 and may also target the silencing H2A variants. In infected cells, histone dynamics were increased in the viral replication compartments, where ICP4 localizes. These results suggest a mechanism whereby ICP4 activates transcription by disrupting, or preventing the formation of, stable silencing nucleosomes on HSV-1 genomes.

The nuclear-replicating DNA viruses of the family herpesviridae cause a variety of diseases. Eight herpesviruses infect humans. Three of them, including herpes simplex virus 1 (HSV-1), belong to the alpha-herpesvirus sub-family. Viruses in this family have the fastest replication cycles of all herpesviruses, producing acute symptoms. During lytic infection, the genomes of HSV-1 associate with histones in more dynamic chromatin than those of the beta- and gamma- herpesviruses. The transcription activator ICP4 is conserved only among alpha-herpesviruses. Although ICP4 is essential, relatively little is known about its mechanisms of action. We have shown that histone dynamics are enhanced in HSV-1 lytically infected cells. Here we show that HSV-1 mutants in ICP4 are deficient in their ability to enhance histone dynamics. ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or DNA. The dynamics of histones were greater in the viral replication compartments, where ICP4 localizes, than in the cellular chromatin. ICP4 may thus mobilize histones away from HSV-1 genomes to activate transcription. Such a mechanism of transcription activation would result in the highly dynamic nature of the viral chromatin and the fast replication cycles, and the acute pathologies, of the alpha-herpesviruses.

• Animals
• Cell Line
• Chlorocebus aethiops
• Chromatin/metabolism
• Fluorescent Antibody Technique
• Gene Expression Regulation, Viral/genetics
• Herpes Simplex/virology
• Herpesvirus 1, Human/genetics
• Herpesvirus 1, Human/metabolism
• Herpesvirus 1, Human/pathogenicity
• Histones/metabolism
• Humans
• Immediate-Early Proteins/metabolism
• Transcription, Genetic
• Transfection
• Vero Cells
• Virus Replication/genetics

• CIHR
• Institute of Infection and Immunity
• Natural Sciences and Engineering Research Council of Canada
• Alberta Innovates - Health Solutions

• DNA
• chromatin
• polynucleotide structures

DNA cytosine methylation is an important epigenetic modification that has significant effects on a variety of biological processes in animals. Avian species hold a crucial position in evolutionary history. In this study, we used whole-genome bisulfite sequencing (MethylC-seq) to generate single base methylation profiles of lungs in two genetically distinct and highly inbred chicken lines (Fayoumi and Leghorn) that differ in genetic resistance to multiple pathogens, and we explored the potential regulatory role of DNA methylation associated with immune response differences between the two chicken lines.

The MethylC-seq was used to generate single base DNA methylation profiles of Fayoumi and Leghorn birds. In addition, transcriptome profiling using RNA–seq from the same chickens and tissues were obtained to interrogate how DNA methylation regulates gene transcription on a genome-wide scale.

The general DNA methylation pattern across different regions of genes was conserved compared to other species except for hyper-methylation of repeat elements, which was not observed in chicken. The methylation level of miRNA and pseudogene promoters was high, which indicates that silencing of these genes may be partially due to promoter hyper-methylation. Interestingly, the promoter regions of more recently evolved genes tended to be more highly methylated, whereas the gene body regions of evolutionarily conserved genes were more highly methylated than those of more recently evolved genes. Immune-related GO (Gene Ontology) terms were significantly enriched from genes within the differentially methylated regions (DMR) between Fayoumi and Leghorn, which implicates DNA methylation as one of the regulatory mechanisms modulating immune response differences between these lines.

This study establishes a single-base resolution DNA methylation profile of chicken lung and suggests a regulatory role of DNA methylation in controlling gene expression and maintaining genome transcription stability. Furthermore, profiling the DNA methylomes of two genetic lines that differ in disease resistance provides a unique opportunity to investigate the potential role of DNA methylation in host disease resistance. Our study provides a foundation for future studies on epigenetic modulation of host immune response to pathogens in chickens.

The online version of this article (doi:10.1186/s12864-015-2098-8) contains supplementary material, which is available to authorized users.

• BAC FISH
• centromere
• chromatin
• pachytene chromosomes
• physical map
• posttranslational histone modifications
• recombination

• Chromosome Mapping
• Chromosomes, Plant/genetics
• Hordeum/genetics

Immunoglobulin E (IgE) plays a key role in allergic asthma and is a clinically validated target for monoclonal antibodies. Therapeutic anti-IgE antibodies block the interaction between IgE and the Fc epsilon (Fcε) receptor, which eliminates or minimizes the allergic phenotype but does not typically curtail the ongoing production of IgE by B cells. We generated high-affinity anti-IgE antibodies (MEDI4212) that have the potential to both neutralize soluble IgE and eliminate IgE-expressing B-cells through antibody-dependent cell-mediated cytotoxicity. MEDI4212 variants were generated that contain mutations in the Fc region of the antibody or alterations in fucosylation in order to enhance the antibody's affinity for FcγRIIIa. All MEDI4212 variants bound to human IgE with affinities comparable to the wild-type (WT) antibody. Each variant was shown to inhibit the interaction between IgE and FcεRI, which translated into potent inhibition of FcγRI-mediated function responses. Importantly, all variants bound similarly to IgE at the surface of membrane IgE expressing cells. However, MEDI4212 variants demonstrated enhanced affinity for FcγRIIIa including the polymorphic variants at position 158. The improvement in FcγRIIIa binding led to increased effector function in cell based assays using both engineered cell lines and class switched human IgE B cells. Through its superior suppression of IgE, we anticipate that effector function enhanced MEDI4212 may be able to neutralize high levels of soluble IgE and provide increased long-term benefit by eliminating the IgE expressing B cells before they differentiate and become IgE secreting plasma cells.

Histone modifiers play essential roles in controlling transcription and organizing eukaryotic genomes into functional domains. Here, we show that Set1, the catalytic subunit of the highly conserved Set1C/COMPASS complex responsible for histone H3K4 methylation (H3K4me), behaves as a repressor of the transcriptome largely independent of Set1C and H3K4me in the fission yeast Schizosaccharomyces pombe. Intriguingly, while Set1 is enriched at highly expressed and repressed loci, Set1 binding levels do not generally correlate with the levels of transcription. We show that Set1 is recruited by the ATF/CREB homolog Atf1 to heterochromatic loci and promoters of stress-response genes. Moreover, we demonstrate that Set1 coordinates with the class II histone deacetylase Clr3 in heterochromatin assembly at prominent chromosomal landmarks and repression of the transcriptome that includes Tf2 retrotransposons, noncoding RNAs, and regulators of development and stress-responses. Our study delineates a molecular framework for elucidating the functional links between transcriptome control and chromatin organization.

DOI:http://dx.doi.org/10.7554/eLife.04506.001

Genes can be turned on or off at different times in an organism's life. In humans, yeast and other eukaryotes, this is mainly controlled by the way DNA is packaged with proteins—known as histones—in a structure called chromatin. Genes that are switched on, or only temporarily switched off, are associated with areas of the genome where the chromatin is loosely packed. In contrast, genes that remain switched off for long periods of time are found in regions—known as heterochromatin—where the chromatin is tightly packed.

There are many enzymes that can modify histones to change the structure of chromatin. One enzyme—called Set1—adds a methyl tag to chromatin, which is known to be associated with genes being switched on. However, Lorenz et al. found that Set1 also has other roles in modifying chromatin in the yeast Schizosaccharomyces pombe.

The experiments found that Set1 helps to keep genes switched off and that this role is largely independent of its ability to add the methyl tag to chromatin. Set1 is recruited to many sites across the genome by another protein called Atf1, which is involved in the cell's response to environmental stresses. Lorenz et al. believe that this helps to put these genes in a ‘poised’ off state so that they are ready to be switched on rapidly if needed.

Set1 also works with another protein that removes acetyl tags—which encourage chromatin to be less tightly packed—from histones. Together, both proteins contribute to the assembly of heterochromatin and keep genes involved in development and stress responses switched off when they are not required.

Collectively, these experiments reveal unexpected and important insights into how Set1—which plays critical roles in many aspects of human health including aging and cancer—works in cells.

DOI:http://dx.doi.org/10.7554/eLife.04506.002

• HDAC
• S. pombe
• atf1
• chromatin
• chromosomes
• evolutionary biology
• genes
• genomics
• heterochromatin
• set1
• transcriptome

Histone modifiers are critical regulators of chromatin-based processes in eukaryotes. The histone methyltransferase Set1, a component of the Set1C/COMPASS complex, catalyzes the methylation at lysine 4 of histone H3 (H3K4me), a hallmark of euchromatin. Here, we show that the fission yeast Schizosaccharomyces pombe Set1 utilizes distinct domain modules to regulate disparate classes of repetitive elements associated with euchromatin and heterochromatin via H3K4me-dependent and -independent pathways. Set1 employs its RNA-binding RRM2 and catalytic SET domains to repress Tf2 retrotransposons and pericentromeric repeats while relying on its H3K4me function to maintain transcriptional repression at the silent mating type (mat) locus and subtelomeric regions. These repressive functions of Set1 correlate with the requirement of Set1C components to maintain repression at the mat locus and subtelomeres while dispensing Set1C in repressing Tf2s and pericentromeric repeats. We show that the contributions of several Set1C subunits to the states of H3K4me diverge considerably from those of Saccharomyces cerevisiae orthologs. Moreover, unlike S. cerevisiae, the regulation of Set1 protein level is not coupled to the status of H3K4me or histone H2B ubiquitination by the HULC complex. Intriguingly, we uncover a genome organization role for Set1C and H3K4me in mediating the clustering of Tf2s into Tf bodies by antagonizing the acetyltransferase Mst1-mediated H3K4 acetylation. Our study provides unexpected insights into the regulatory intricacies of a highly conserved chromatin-modifying complex with diverse roles in genome control.

Methylation of histone H3 at lysine 4 (H3K4me) is a well-documented mark associated with euchromatin. In this study, we investigate the contributions of the histone methyltransferase Set1 (KMT2) and its associated Set1C/COMPASS complex in the fission yeast Schizosaccharomyces pombe to histone H3 lysine 4 methylation (H3K4me), transcriptional repression, and genome organization. We show that Set1 exhibits multiple modes of transcriptional repression at different types of repetitive elements, requiring distinct domains of Set1 and other Set1C subunits. Despite high conservation of subunits between the S. pombe and S. cerevisiae Set1C complexes, there are considerable differences in contributions to H3K4me by several individual subunits. Furthermore, unlike a recent report in S. cerevisiae, the abundance of Set1 proteins in S. pombe is generally not coupled to either the status of H3K4 methylation or H2B ubiquitination, further highlighting critical differences in Set1 regulation between the two yeast species. We describe a role for the Set1C complex in the nuclear organization of dispersed retrotransposons into Tf bodies. Set1C maintains Tf body integrity by employing H3K4me to antagonize the activities of the H3K4 acetyltransferase Mst1. Collectively, our findings dramatically expand the regulatory landscape controlled by the Set1C complex, an important and highly conserved chromatin-modifying complex with diverse roles in genome control and development.

• DNA Methylation/genetics
• Euchromatin/genetics
• Genome, Fungal
• Histone Demethylases/genetics
• Histone-Lysine N-Methyltransferase/genetics
• Histones/genetics
• In Situ Hybridization, Fluorescence
• Multiprotein Complexes
• Protein Structure, Tertiary
• Schizosaccharomyces/genetics
• Schizosaccharomyces pombe Proteins/genetics
• Transcription Factors/genetics
• Ubiquitination