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Laura Brueckner, Joris van Arensbergen, Waseem Akhtar, Ludo Pagie, Bas van Steensel
BACKGROUND: Chromatin proteins control gene activity in a concerted manner. We developed a high-throughput assay to study the effects of the local chromatin environment on the regulatory activity of a protein of interest. The assay combines a previously reported multiplexing strategy based on barcoded randomly integrated reporters with Gal4-mediated tethering. We applied the assay to Drosophila heterochromatin protein 1a (HP1a), which is mostly known as a repressive protein but has also been linked to transcriptional activation...
2016: Epigenetics & Chromatin
Caitlin G Howe, Xinhua Liu, Megan N Hall, Vesna Ilievski, Marie A Caudill, Olga Malysheva, Angela M Lomax-Luu, Faruque Parvez, Abu B Siddique, Hasan Shahriar, Mohammad N Uddin, Tariqul Islam, Joseph H Graziano, Max Costa, Mary V Gamble
BACKGROUND: Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. METHODS: We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMCs) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults...
October 20, 2016: Cancer Epidemiology, Biomarkers & Prevention
Yuan Fang, Lei Wang, Ximeng Wang, Qi You, Xiucai Pan, Jin Xiao, Xiu-E Wang, Yufeng Wu, Zhen Su, Wenli Zhang
BACKGROUND: Bidirectional gene pairs are highly abundant and mostly co-regulated in eukaryotic genomes. The structural features of bidirectional promoters (BDPs) have been well studied in yeast, humans and plants. However, the underlying mechanisms responsible for the coexpression of BDPs remain understudied, especially in plants. RESULTS: Here, we characterized chromatin features associated with rice BDPs. Several unique chromatin features were present in rice BDPs but were missing from unidirectional promoters (UDPs), including overrepresented active histone marks, canonical nucleosomes and underrepresented H3K27me3...
September 30, 2016: BMC Genomics
Stefanie Rosa, Susan Duncan, Caroline Dean
Antisense transcription through genic regions is pervasive in most genomes; however, its functional significance is still unclear. We are studying the role of antisense transcripts (COOLAIR) in the cold-induced, epigenetic silencing of Arabidopsis FLOWERING LOCUS C (FLC), a regulator of the transition to reproduction. Here we use single-molecule RNA FISH to address the mechanistic relationship of FLC and COOLAIR transcription at the cellular level. We demonstrate that while sense and antisense transcripts can co-occur in the same cell they are mutually exclusive at individual loci...
October 7, 2016: Nature Communications
Hong-Ren Yu, You-Lin Tain, Jiunn-Ming Sheen, Mao-Meng Tiao, Chih-Cheng Chen, Ho-Chang Kuo, Pi-Lien Hung, Kai-Sheng Hsieh, Li-Tung Huang
Overexposure to prenatal glucocorticoid (GC) disturbs hypothalamic-pituitary-adrenocortical axis-associated neuroendocrine metabolism and susceptibility to metabolic syndrome. A high-fat (HF) diet is a major environmental factor that can cause metabolic syndrome. We aimed to investigate whether prenatal GC plus a postnatal HF diet could alter immune programming in rat offspring. Pregnant Sprague-Dawley rats were given intraperitoneal injections of dexamethasone or saline at 14-21 days of gestation. Male offspring were then divided into four groups: vehicle, prenatal dexamethasone exposure, postnatal HF diet (VHF), and prenatal dexamethasone exposure plus a postnatal HF diet (DHF)...
2016: International Journal of Molecular Sciences
Jennifer R Bermick, Nathalie J Lambrecht, Aaron D denDekker, Steven L Kunkel, Nicholas W Lukacs, Cory M Hogaboam, Matthew A Schaller
BACKGROUND: Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens. This makes them uniquely susceptible to infections, but the factors regulating neonatal-specific immune responses are poorly understood. Epigenetics, including histone modifications, can activate or silence gene transcription by modulating chromatin structure and stability without affecting the DNA sequence itself and are potentially modifiable. Histone modifications are known to regulate immune cell differentiation and function in adults but have not been well studied in neonates...
2016: Clinical Epigenetics
Yanchao Liu, Hong Wu, Yu Yu, Ying Huang
MRG proteins are conserved during evolution in fungi, flies, mammals and plants, and they can exhibit diversified functions. The animal MRGs were found to form various complexes to activate gene expression. Plant MRG1/2 and MRG702 were reported to be involved in the regulation of flowering time via binding to H3K36me3-marked flowering genes. Herein, we determined the crystal structure of MRG701 chromodomain (MRG701(CD)). MRG701(CD) forms a novel dimerization fold both in crystal and in solution. Moreover, we found that the dimerization of MRG chromodomains is conserved in green plants...
September 8, 2016: Protein & Cell
Kun Zhu, Pin-Ji Lei, Lin-Gao Ju, Xiang Wang, Kai Huang, Bo Yang, Changwei Shao, Yuan Zhu, Gang Wei, Xiang-Dong Fu, Lianyun Li, Min Wu
Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 polyubiquitination both in vivo and in vitro ChIP-Seq analysis and biochemical experiments demonstrate that modulation of SPOP expression confers differential H3K36me3 on SETD2 target genes, and induce H3K36me3-coupled alternative splicing events...
September 9, 2016: Nucleic Acids Research
Naoki Iwamori, Kaoru Tominaga, Tetsuya Sato, Kevin Riehle, Tokuko Iwamori, Yasuyuki Ohkawa, Cristian Coarfa, Etsuro Ono, Martin M Matzuk
Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Amato J Giaccia
The set domain containing 2 (SETD2) histone methyltransferase, located at 3p2, specifically trimethylates lysine 36 of histone H3 (H3K36me3). H3K36me3 is an active mark involved in transcriptional elongation and RNA processing, and a key regulator of DNA repair. In fact, SETD2 is the only methyltransferase that "writes" the H3K36me3 mark. Recent results from Park et al have found a new role for SETD2 in the methylation of K40 of alpha-tubulin. Loss of SETD2 abolishes methylation of K40 of alpha-tubulin, and results in a dysfunctional mitotic spindle and abnormalities in cytokinesis...
August 15, 2016: Molecular Cancer Research: MCR
Kathryn E Hacker, Catherine C Fahey, Stephen A Shinsky, Yun-Chen J Chiang, Julia V DiFiore, Deepak Kumar Jha, Andy H Vo, Jordan A Shavit, Ian J Davis, Brian D Strahl, W Kimryn Rathmell
The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers...
September 30, 2016: Journal of Biological Chemistry
In Young Park, Reid T Powell, Durga Nand Tripathi, Ruhee Dere, Thai H Ho, T Lynne Blasius, Yun-Chen Chiang, Ian J Davis, Catherine C Fahey, Kathryn E Hacker, Kristen J Verhey, Mark T Bedford, Eric Jonasch, W Kimryn Rathmell, Cheryl Lyn Walker
Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules...
August 11, 2016: Cell
Ronen Sadeh, Roee Launer-Wachs, Hava Wandel, Ayelet Rahat, Nir Friedman
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) has been instrumental to our current view of chromatin structure and function. It allows genome-wide mapping of histone marks, which demarcate biologically relevant domains. However, ChIP-seq is an ensemble measurement reporting the average occupancy of individual marks in a cell population. Consequently, our understanding of the combinatorial nature of chromatin states relies almost exclusively on correlation between the genomic distributions of individual marks...
September 15, 2016: Molecular Cell
Lorenzo Rinaldi, Debayan Datta, Judit Serrat, Lluis Morey, Guiomar Solanas, Alexandra Avgustinova, Enrique Blanco, José Ignacio Pons, David Matallanas, Alex Von Kriegsheim, Luciano Di Croce, Salvador Aznar Benitah
The genome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells are unknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histone H3K36me3-dependent manner to the most active enhancers and are required to produce their associated enhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define the ectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3b differ in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3b promotes DNA methylation along the body of the enhancer...
October 6, 2016: Cell Stem Cell
Daniel Dominguez, Yi-Hsuan Tsai, Nicholas Gomez, Deepak Kumar Jha, Ian Davis, Zefeng Wang
Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transcriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles (>2.3 billion paired reads), we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators...
August 2016: Cell Research
Natalie R Powers, Emil D Parvanov, Christopher L Baker, Michael Walker, Petko M Petkov, Kenneth Paigen
In many mammals, including humans and mice, the zinc finger histone methyltransferase PRDM9 performs the first step in meiotic recombination by specifying the locations of hotspots, the sites of genetic recombination. PRDM9 binds to DNA at hotspots through its zinc finger domain and activates recombination by trimethylating histone H3K4 on adjacent nucleosomes through its PR/SET domain. Recently, the isolated PR/SET domain of PRDM9 was shown capable of also trimethylating H3K36 in vitro, raising the question of whether this reaction occurs in vivo during meiosis, and if so, what its function might be...
June 2016: PLoS Genetics
Zhixiang Wang, Yuan Liu, Yong Xue, Haiyan Hu, Jieyu Ye, Xiaodong Li, Zhigang Lu, Fanyi Meng, Shuang Liang
Berberine, an isoquinoline plant alkaloid, exhibits a wide range of biochemical and pharmacological effects. However, the precise mechanism of these bioactivities remains poorly understood. In this study, we found significant similarity between berberine and two epigenetic modulators (CG-1521 and TSA). Reverse-docking using berberine as a ligand identified lysine-N-methyltransferase as a putative target of berberine. These findings suggested the potential role of berberine in epigenetic modulation. The results of PCR array analysis of epigenetic chromatin modification enzymes supported our hypothesis...
October 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Jun Li, Joost Kluiver, Jan Osinga, Helga Westers, Maaike B van Werkhoven, Marc A Seelen, Rolf H Sijmons, Anke van den Berg, Klaas Kok
SET domain-containing 2 (SETD2) is responsible for the trimethylation of histone H3 lysine36 (H3K36me3) and is one of the genes most frequently mutated in clear cell renal cell carcinoma (ccRCC). It is located at 3p21, one copy of which is lost in the majority of ccRCC tumors, suggesting that SETD2 might function as a tumor suppressor gene. However, the manner in which loss of SETD2 contributes to ccRCC development has not been studied in renal primary tubular epithelial cells (PTECs). Therefore, we studied the consequences of SETD2 knockdown through lentiviral shRNA in human PTECs...
June 2016: Neoplasia: An International Journal for Oncology Research
Marianne Terndrup Pedersen, Susanne Marije Kooistra, Aliaksandra Radzisheuskaya, Anne Laugesen, Jens Vilstrup Johansen, Daniel Geoffrey Hayward, Jakob Nilsson, Karl Agger, Kristian Helin
Chromatin-associated proteins are essential for the specification and maintenance of cell identity. They exert these functions through modulating and maintaining transcriptional patterns. To elucidate the functions of the Jmjd2 family of H3K9/H3K36 histone demethylases, we generated conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). We report that while individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions...
July 15, 2016: EMBO Journal
Gerald O Hunter, Melanie J Fox, Whitney R Smith-Kinnaman, Madelaine Gogol, Brian Fleharty, Amber L Mosley
In eukaryotes, the C-terminal domain (CTD) of Rpb1 contains a heptapeptide repeat sequence of (Y1S2P3T4S5P6S7)n that undergoes reversible phosphorylation through the opposing action of kinases and phosphatases. Rtr1 is a conserved protein that colocalizes with RNA polymerase II (RNAPII) and has been shown to be important for the transition from elongation to termination during transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes. In this study, we show that Rtr1 is a global regulator of the CTD code with deletion of RTR1 causing genome-wide changes in Ser5-P CTD phosphorylation and cotranscriptional histone H3 lysine 36 trimethylation (H3K36me3)...
September 1, 2016: Molecular and Cellular Biology
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