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TCDD induces multigenerational alterations in the expression ofmicroRNA in the thymus through epigenetic modifications
Singh Narendra P et al.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand, is an environmental contaminant that is known for mediating toxicity across generations. However, whether TCDD can induce multigenerational changes in the expression of miRNAs (miRs) has not been previously studied. In the current study, we investigate... |
Identification of genomic binding sites and direct target genes for thetranscription factor DDIT3/CHOP.
Osman A. et al.
DDIT3 is a tightly regulated basic leucine zipper (bZIP) transcription factor and key regulator in cellular stress responses. It is involved in a variety of pathological conditions and may cause cell cycle block and apoptosis. It is also implicated in differentiation of some specialized cell types and as an oncogene... |
Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis byregulating the respiratory process.
Gao X.et al.
Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that... |
Dominant role of DNA methylation over H3K9me3 for IAP silencingin endoderm.
Wang Z. et al.
Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to... |
HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependentgene repression in murine erythroleukaemia.
Gregoricchio S. et al.
Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 ... |
Dual role of histone variant H3.3B in spermatogenesis: positiveregulation of piRNA transcription and implication in X-chromosomeinactivation.
Fontaine E. et al.
The histone variant H3.3 is encoded by two distinct genes, H3f3a and H3f3b, exhibiting identical amino-acid sequence. H3.3 is required for spermatogenesis, but the molecular mechanism of its spermatogenic function remains obscure. Here, we have studied the role of each one of H3.3A and H3.3B proteins in spermatogene... |
TBX2 acts as a potent transcriptional silencer of tumour suppressor genesthrough interaction with the CoREST complex to sustain theproliferation of breast cancers.
McIntyre A.J. et al.
Chromosome 17q23 amplification occurs in 20\% of primary breast tumours and is associated with poor outcome. The TBX2 gene is located on 17q23 and is often over-expressed in this breast tumour subset. TBX2 is an anti-senescence gene, promoting cell growth and survival through repression of Tumour Suppressor Genes (T... |
Epigenetic Mechanisms Mediating Cell State Transitions in Chondrocytes
Wuelling M. et al.
Epigenetic modifications play critical roles in regulating cell lineage differentiation, but the epigenetic mechanisms guiding specific differentiation steps within a cell lineage have rarely been investigated. To decipher such mechanisms, we used the defined transition from proliferating (PC) into hypertrophic chon... |
The CpG Island-Binding Protein SAMD1 Contributes to anUnfavorable Gene Signature in HepG2 Hepatocellular CarcinomaCells.
Simon C. et al.
The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-... |
Local euchromatin enrichment in lamina-associated domains anticipatestheir repositioning in the adipogenic lineage.
Madsen-Østerbye J. et al.
BACKGROUND: Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confer structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains, however, elusive. RESULTS: We examined changes in t... |
CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.
Bommi-Reddy A. et al.
Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach... |
NuA4 and H2A.Z control environmental responses and autotrophicgrowth in Arabidopsis
Bieluszewski T. et al.
Nucleosomal acetyltransferase of H4 (NuA4) is an essential transcriptional coactivator in eukaryotes, but remains poorly characterized in plants. Here, we describe Arabidopsis homologs of the NuA4 scaffold proteins Enhancer of Polycomb-Like 1 (AtEPL1) and Esa1-Associated Factor 1 (AtEAF1). Loss of AtEAF1 results in ... |
Epromoters function as a hub to recruit key transcription factorsrequired for the inflammatory response
Santiago-Algarra D. et al.
Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a... |
Decreased PRC2 activity supports the survival of basal-like breastcancer cells to cytotoxic treatments
Mieczkowska IK et al.
Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC ... |
Ago1 controls myogenic differentiation by regulating eRNA-mediatedCBP-guided epigenome reprogramming.
Fallatah Bodor et al.
The role of chromatin-associated RNAi components in the nucleus of mammalian cells and in particular in the context of developmental programs remains to be elucidated. Here, we investigate the function of nuclear Argonaute 1 (Ago1) in gene expression regulation during skeletal muscle differentiation. We show that Ag... |
Alveolar macrophages from persons living with HIV show impairedepigenetic response to Mycobacterium tuberculosis.
Correa-Macedo Wilian et al.
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV a... |
INTS11 regulates hematopoiesis by promoting PRC2 function.
Zhang Peng et al.
INTS11, the catalytic subunit of the Integrator (INT) complex, is crucial for the biogenesis of small nuclear RNAs and enhancer RNAs. However, the role of INTS11 in hematopoietic stem and progenitor cell (HSPC) biology is unknown. Here, we report that INTS11 is required for normal hematopoiesis and hematopoietic-spe... |
The related coactivator complexes SAGA and ATAC control embryonicstem cell self-renewal through acetyltransferase-independent mechanisms
Fischer Veronique et al.
SUMMARY SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada-two-A-containing) are two related coactivator complexes, sharing the same histone acetyltransferase (HAT) subunit. The HAT activities of SAGA and ATAC are required for metazoan development, but the role of these complexes in RNA polymerase II transcription ... |
Altered Chromatin States Drive Cryptic Transcription in AgingMammalian Stem Cells.
McCauley Brenna S et al.
A repressive chromatin state featuring trimethylated lysine 36 on histone H3 (H3K36me3) and DNA methylation suppresses cryptic transcription in embryonic stem cells. Cryptic transcription is elevated with age in yeast and nematodes, and reducing it extends yeast lifespan, though whether this occurs in mammals is unk... |
Metabolically controlled histone H4K5 acylation/acetylation ratiodrives BRD4 genomic distribution.
Gao M. et al.
In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations' specific roles. Here, by... |
Heterogeneity of neurons reprogrammed from spinal cord astrocytes by theproneural factors Ascl1 and Neurogenin2
Kempf J. et al.
Summary Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astro... |
Lasp1 regulates adherens junction dynamics and fibroblast transformationin destructive arthritis
Beckmann D. et al.
The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrativ... |
The SAM domain-containing protein 1 (SAMD1) acts as a repressivechromatin regulator at unmethylated CpG islands
Stielow B. et al.
CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that direct... |
Waves of sumoylation support transcription dynamics during adipocytedifferentiation
Zhao, X. et al.
Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, little is known about the mechanisms that orchestrate the dramatic transcriptional changes leading to adipocyte differentiation. We investigated ... |
Polycomb Repressive Complex 2 and KRYPTONITE regulate pathogen-inducedprogrammed cell death in Arabidopsis.
Dvořák Tomaštíková E. et al.
The Polycomb Repressive Complex 2 (PRC2) is well-known for its role in controlling developmental transitions by suppressing the premature expression of key developmental regulators. Previous work revealed that PRC2 also controls the onset of senescence, a form of developmental programmed cell death (PCD) in plants. ... |
An integrated multi-omics analysis identifies prognostic molecularsubtypes of non-muscle-invasive bladder cancer
Lindskrog Sia Viborg et al.
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, ... |
Loss of SETD1B results in the redistribution of genomic H3K4me3 in theoocyte
Hanna, C. W. et al.
Histone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 are essential for oogenesis. We investigated cha... |
VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer
Poulose N. et al.
Androgen receptor (AR) is a major driver of prostate cancer (PCa) initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyses the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often up-regulated in PCa with its expression correlated w... |
JAZF1, A Novel p400/TIP60/NuA4 Complex Member, Regulates H2A.ZAcetylation at Regulatory Regions.
Procida, Tara and Friedrich, Tobias and Jack, Antonia P M and Peritore,Martina and Bönisch, Clemens and Eberl, H Christian and Daus, Nadine andKletenkov, Konstantin and Nist, Andrea and Stiewe, Thorsten and Borggrefe,Tilman and Mann, Matthias and Bartk
Histone variants differ in amino acid sequence, expression timing and genomic localization sites from canonical histones and convey unique functions to eukaryotic cells. Their tightly controlled spatial and temporal deposition into specific chromatin regions is accomplished by dedicated chaperone and/or remodeling c... |
Epigenetic impairment and blunted transcriptional response to Mycobacteriumtuberculosis of alveolar macrophages from persons living with HIV
Correa-Macedo, W. et al.
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV a... |
Histone demethylase JMJD2B/KDM4B regulates transcriptional program viadistinctive epigenetic targets and protein interactors for the maintenanceof trophoblast stem cells.
Mak, Kylie Hin-Man et al.
Trophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we ... |
Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture.
Yusufova, Nevin and Kloetgen, Andreas and Teater, Matt and Osunsade,Adewola and Camarillo, Jeannie M and Chin, Christopher R and Doane, AshleyS and Venters, Bryan J and Portillo-Ledesma, Stephanie and Conway, Josephand Phillip, Jude M and Elemento, Oli
Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B-E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphoma... |
Multi-omic comparison of Alzheimer's variants in human ESC-derivedmicroglia reveals convergence at APOE.
Liu, Tongfei and Zhu, Bing and Liu, Yan and Zhang, Xiaoming and Yin, Junand Li, Xiaoguang and Jiang, LuLin and Hodges, Andrew P and Rosenthal, SaraBrin and Zhou, Lisa and Yancey, Joel and McQuade, Amanda and Blurton-Jones,Mathew and Tanzi, Rudolph E an
Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and cura... |
A genetic variant controls interferon-β gene expression in human myeloidcells by preventing C/EBP-β binding on a conserved enhancer.
Assouvie, Anaïs and Rotival, Maxime and Hamroune, Juliette and Busso,Didier and Romeo, Paul-Henri and Quintana-Murci, Lluis and Rousselet,Germain
Interferon β (IFN-β) is a cytokine that induces a global antiviral proteome, and regulates the adaptive immune response to infections and tumors. Its effects strongly depend on its level and timing of expression. Therefore, the transcription of its coding gene IFNB1 is strictly controlled. We have previous... |
Increased H3K4me3 methylation and decreased miR-7113-5p expression lead toenhanced Wnt/β-catenin signaling in immune cells from PTSD patientsleading to inflammatory phenotype.
Bam, Marpe and Yang, Xiaoming and Busbee, Brandon P and Aiello, Allison Eand Uddin, Monica and Ginsberg, Jay P and Galea, Sandro and Nagarkatti,Prakash S and Nagarkatti, Mitzi
BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder accompanied by chronic peripheral inflammation. What triggers inflammation in PTSD is currently unclear. In the present study, we identified potential defects in signaling pathways in peripheral blood mononuclear cells (PBMCs) from individual... |
Trans- and cis-acting effects of Firre on epigenetic features of theinactive X chromosome.
Fang, He and Bonora, Giancarlo and Lewandowski, Jordan P and Thakur,Jitendra and Filippova, Galina N and Henikoff, Steven and Shendure, Jay andDuan, Zhijun and Rinn, John L and Deng, Xinxian and Noble, William S andDisteche, Christine M
Firre encodes a lncRNA involved in nuclear organization. Here, we show that Firre RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of t... |
The histone H2B ubiquitin ligase RNF40 is required for HER2-drivenmammary tumorigenesis.
Wegwitz, Florian and Prokakis, Evangelos and Pejkovska, Anastasija andKosinsky, Robyn Laura and Glatzel, Markus and Pantel, Klaus and Wikman,Harriet and Johnsen, Steven A
The HER2-positive breast cancer subtype (HER2-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment str... |
Polycomb Repressive Complex 2-mediated histone modification H3K27me3 isassociated with embryogenic potential in Norway spruce.
Nakamura, Miyuki and Batista, Rita A and Köhler, Claudia and Hennig, Lars
Epigenetic reprogramming during germ cell formation is essential to gain pluripotency and thus embryogenic potential. The histone modification H3K27me3, which is catalysed by the Polycomb repressive complex 2 (PRC2), regulates important developmental processes in both plants and animals, and defects in PRC2 componen... |
Age-associated cryptic transcription in mammalian stem cells is linked topermissive chromatin at cryptic promoters
McCauley B. S. et al.
Suppressing spurious cryptic transcription by a repressive intragenic chromatin state featuring trimethylated lysine 36 on histone H3 (H3K36me3) and DNA methylation is critical for maintaining self-renewal capacity in mouse embryonic stem cells. In yeast and nematodes, such cryptic transcription is elevated with age... |
RNF40 exerts stage-dependent functions in differentiating osteoblasts andis essential for bone cell crosstalk.
Najafova, Zeynab and Liu, Peng and Wegwitz, Florian and Ahmad, Mubashir andTamon, Liezel and Kosinsky, Robyn Laura and Xie, Wanhua and Johnsen, StevenA and Tuckermann, Jan
The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblas... |
Epigenetic regulation of the lineage specificity of primary human dermallymphatic and blood vascular endothelial cells.
Tacconi, Carlotta and He, Yuliang and Ducoli, Luca and Detmar, Michael
Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vasc... |
Combined treatment with CBP and BET inhibitors reverses inadvertentactivation of detrimental super enhancer programs in DIPG cells.
Wiese, M and Hamdan, FH and Kubiak, K and Diederichs, C and Gielen, GHand Nussbaumer, G and Carcaboso, AM and Hulleman, E and Johnsen, SA andKramm, CM
Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetyla... |
Exploring the virulence gene interactome with CRISPR/dCas9 in the humanmalaria parasite.
Bryant, JM and Baumgarten, S and Dingli, F and Loew, D and Sinha, A andClaës, A and Preiser, PR and Dedon, PC and Scherf, A
Mutually exclusive expression of the var multigene family is key to immune evasion and pathogenesis in Plasmodium falciparum, but few factors have been shown to play a direct role. We adapted a CRISPR-based proteomics approach to identify novel factors associated with var genes in their natural chromatin context. Ca... |
Tissue-Specific In Vivo Biotin Chromatin Immunoprecipitation withSequencing in Zebrafish and Chicken
Lukoseviciute, Martyna and Ling, Irving T.C. and Senanayake, Upeka andCandido-Ferreira, Ivan and Taylor, Gunes and Williams, Ruth M. andSauka-Spengler, Tatjana
Chromatin immunoprecipitation with sequencing (ChIP-seq) has been instrumental in understanding transcription factor (TF) binding during gene regulation. ChIP-seq requires specific antibodies against desired TFs, which are not available for numerous species. Here, we describe a tissue-specific biotin ChIP-seq protoc... |
The gut microbiome switches mutant p53 from tumour-suppressive tooncogenic.
Kadosh, E and Snir-Alkalay, I and Venkatachalam, A and May, S and Lasry, Aand Elyada, E and Zinger, A and Shaham, M and Vaalani, G and Mernberger, Mand Stiewe, T and Pikarsky, E and Oren, M and Ben-Neriah, Y
Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal c... |
Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination.
Wüst HM, Wegener A, Fröb F, Hartwig AC, Wegwitz F, Kari V, Schimmel M, Tamm ER, Johnsen SA, Wegner M, Sock E
Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. How... |
Battle of the sex chromosomes: competition between X- and Y-chromosomeencoded proteins for partner interaction and chromatin occupancy drivesmulti-copy gene expression and evolution in muroid rodents.
Moretti, C and Blanco, M and Ialy-Radio, C and Serrentino, ME and Gobé,C and Friedman, R and Battail, C and Leduc, M and Ward, MA and Vaiman, Dand Tores, F and Cocquet, J
Transmission distorters (TDs) are genetic elements that favor their own transmission to the detriments of others. Slx/Slxl1 (Sycp3-like-X-linked and Slx-like1) and Sly (Sycp3-like-Y-linked) are TDs which have been co-amplified on the X and Y chromosomes of Mus species. They are involved in an intragenomic conflict i... |
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats.
Doskey CM, Fader KA, Nault R, Lydic T, Matthews J, Potter D, Sharratt B, Williams K, Zacharewski T
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent hepatic effects including lipid accumulation, inflammation, and fibrosis. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid me... |
Epigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment.
Eckersley-Maslin MA, Parry A, Blotenburg M, Krueger C, Ito Y, Franklin VNR, Narita M, D'Santos CS, Reik W
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 lo... |
Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.
Paliouras AR, Buzzetti M, Shi L, Donaldson IJ, Magee P, Sahoo S, Leong HS, Fassan M, Carter M, Di Leva G, Krebs MG, Blackhall F, Lovly CM, Garofalo M
A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resis... |
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