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https://www.readbyqxmd.com/read/28642444/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#1
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28633016/mll-wdr5-complex-regulates-kif2a-localization-to-ensure-chromosome-congression-and-proper-spindle-assembly-during-mitosis
#2
Aamir Ali, Sailaja Naga Veeranki, Akash Chinchole, Shweta Tyagi
Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28630472/smyd3-promotes-homologous-recombination-via-regulation-of-h3k4-mediated-gene-expression
#3
Yun-Ju Chen, Cheng-Hui Tsai, Pin-Yu Wang, Shu-Chun Teng
SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630052/infection-exposure-promotes-etv6-runx1-precursor-b-cell-leukemia-via-impaired-h3k4-demethylases
#4
Guillermo Rodríguez-Hernández, Julia Hauer, Alberto Martín-Lorenzo, Daniel Schäfer, Christoph Bartenhagen, Idoia García-Ramírez, Franziska Auer, Ines Gonzalez-Herrero, Lucia Ruiz-Roca, Michael Gombert, Vera Okpanyi, Ute Fischer, Cai Chen, Martin Dugas, Sanil Bhatia, René M Linka, Marta Garcia-Suquia, María V Rascón-Trincado, Angel Garcia-Sanchez, Oscar Blanco, Maria Begona Garcia-Cenador, Francisco Javier Garcia-Criado, César Cobaleda, Diego Alonso-López, Javier De Las Rivas, Markus Müschen, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt
<p>ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL...
June 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/28627608/silencing-of-lsd1-gene-modulates-histone-methylation-and-acetylation-and-induces-the-apoptosis-of-jeko-1-and-molt-4-cells
#5
Zhong-Kai Zou, Yi-Qun Huang, Yong Zou, Xu-Ke Zheng, Xu-Dong Ma
Lysine-specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics; however, the pathological roles of its dysfunction in mantle cell lymphoma (MCL) and T-cell acute lymphoblastic leukemia remain to be elucidated. In this study, we evaluated LSD1, and histone H3 lysine 4 (H3K4)me1 and H3K4me2 expression in patients with MCL and silenced LSD1 in JeKo‑1 and MOLT‑4 cells, in order to define its role in JeKo‑1 and MOLT‑4 cell proliferation and apoptosis. We retrospectively analyzed the protein expression of LSD1, and mono- and dimethylated H3K4 (H3K4me1 and H3K4me2), and cyclin D1 and Ki67 in 30 cases of MCL by immunohistochemistry...
June 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28619824/the-histone-3-lysine-4-methyltransferase-setd1b-is-a-maternal-effect-gene-required-for-the-oogenic-gene-expression-program
#6
David Brici, Qinyu Zhang, Susanne Reinhardt, Andreas Dahl, Hella Hartmann, Kerstin Schmidt, Neha Goveas, Jiahao Huang, Lenka Gahurova, Gavin Kelsey, Konstantinos Anastassiadis, A Francis Stewart, Andrea Kranz
Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility. Oocyte specific Gdf9iCre conditional knockout (Setd1b(Gdf9) cKO) ovaries develop through all stages however follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle...
June 15, 2017: Development
https://www.readbyqxmd.com/read/28609657/ack1-tnk2-regulates-histone-h4-tyr88-phosphorylation-and-ar-gene-expression-in-castration-resistant-prostate-cancer
#7
Kiran Mahajan, Pavani Malla, Harshani R Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J Lawrence, Nupam P Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28603984/discovery-of-a-highly-potent-cell-permeable-macrocyclic-peptidomimetic-mm-589-targeting-the-wd-repeat-domain-5-protein-wdr5-mixed-lineage-leukemia-mll-protein-protein-interaction
#8
Hacer Karatas, Yangbing Li, Liu Liu, Jiao Ji, Shirley Lee, Yong Chen, Jiuling Yang, Liyue Huang, Denzil Bernard, Jing Xu, Elizabeth C Townsend, Fang Cao, Xu Ran, Xiaoqin Li, Bo Wen, Duxin Sun, Jeanne A Stuckey, Ming Lei, Yali Dou, Shaomeng Wang
We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401...
June 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28601897/histone-methylation-in-the-freeze-tolerant-wood-frog-rana-sylvatica
#9
Liam J Hawkins, Kenneth B Storey
Freeze-tolerant animals survive sub-zero temperatures and long-term starvation associated with the winter by lowering their metabolic rate using a variety of transcriptional, translational, and post-translational regulatory methods. Histone methylation is one mechanism that is known to regulate gene expression at the transcriptional level. Here, we measured relative protein levels of seven histone methyltransferases (SMYD2, SETD7, ASH2L, RBBP5, SUV39H1, EHMT2, and SET8), four methylated histone H3 residues (H3K4me1, H3K9me3, H3K27me1, and H3K36me2), the methyltransferase activity on H3K4, and methylation of p53 (p53K370me2 and p53K372me1) in the skeletal muscle and liver of the freeze-tolerant wood frog (Rana sylvatica) during the freeze-thaw cycle...
June 10, 2017: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
https://www.readbyqxmd.com/read/28601046/lsd1-knockdown-reveals-novel-histone-lysine-methylation-in-human-breast-cancer-mcf-7-cells
#10
Yue Jin, Bo Huo, Xueqi Fu, Zhongyi Cheng, Jun Zhu, Yu Zhang, Tian Hao, Xin Hu
Histone lysine methylation, which plays an important role in the regulation of gene expression, genome stability, chromosome conformation and cell differentiation, is a dynamic process that is collaboratively regulated by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). LSD1, the first identified KDMs, catalyzes the demethylation of mono- and di-methylated H3K4 and H3K9. Here, we systematically investigated the effects of LSD1 knockdown on histone methylations. Surprisingly, in addition to H3K4 and H3K9, the methylation level on other histone lysines, such as H3K27, H3K36 and H3K79, are also increased...
June 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28598443/ash1l-and-lnc-smad3-coordinate-smad3-locus-accessibility-to-modulate-itreg-polarization-and-t-cell-autoimmunity
#11
Meng Xia, Juan Liu, Shuxun Liu, Kun Chen, Hongyu Lin, Minghong Jiang, Xiaoqing Xu, Yiquan Xue, Wei Liu, Yan Gu, Xiang Zhang, Zhiqing Li, Lin Yi, Youcun Qian, Chen Zhou, Ru Li, Xuan Zhang, Zhanguo Li, Xuetao Cao
Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-β-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription...
June 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28572115/histone-demethylase-kdm5a-regulates-the-zmynd8-nurd-chromatin-remodeler-to-promote-dna-repair
#12
Fade Gong, Thomas Clouaire, Marion Aguirrebengoa, Gaëlle Legube, Kyle M Miller
Upon DNA damage, histone modifications are dynamically reshaped to accommodate DNA damage signaling and repair within chromatin. In this study, we report the identification of the histone demethylase KDM5A as a key regulator of the bromodomain protein ZMYND8 and NuRD (nucleosome remodeling and histone deacetylation) complex in the DNA damage response. We observe KDM5A-dependent H3K4me3 demethylation within chromatin near DNA double-strand break (DSB) sites. Mechanistically, demethylation of H3K4me3 is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage...
June 1, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28550207/atx3-atx4-and-atx5-encode-putative-h3k4-methyltransferases-and-are-critical-for-plant-development
#13
Liqun Chen, Jinhong Luo, Zhenhai Cui, Ming Xue, Li Wang, Xiaoyu Zhang, Wojtek P Pawlowski, Yan He
Methylation of lysine residues in the tail of the H3 histone is a key regulator of chromatin state and gene expression, conferred by a large family of enzymes containing an evolutionarily-conserved SET domain. One of the main types of SET domain proteins are those controlling H3K4 di- and trimethylation. The genome of Arabidopsis encodes 12 such proteins, including five ARABIDOPSIS TRITHORAX (ATX) proteins and seven ATX-Related (ATXR) proteins. Here we examined three until-now-unexplored ATX proteins, ATX3, ATX4, and ATX5...
May 26, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28517045/set-domain-group701-encodes-a-h3k4-methytransferase-and-regulates-multiple-key-processes-of-rice-plant-development
#14
Kunpeng Liu, Yu Yu, Aiwu Dong, Wen-Hui Shen
Chromatin-based epigenetic information plays an important role in developmental gene regulation, in response to environment, and in natural variation of gene expression levels. Histone H3 lysine 4 di/trimethylation (H3K4me2/3) is abundant in euchromatin and is generally associated with transcriptional activation. Strikingly, however, enzymes catalyzing H3K4me2/3 remain poorly characterized in crops so far. Here, we investigated the function of the rice SET DOMAIN GROUP 701 (SDG701) gene by molecular and biochemical characterization of the gene product, and by studying effects of its loss or gain of function on plant growth and development...
May 18, 2017: New Phytologist
https://www.readbyqxmd.com/read/28515277/histone-chaperone-hira-regulates-neural-progenitor-cell-proliferation-and-neurogenesis-via-%C3%AE-catenin
#15
Yanxin Li, Jianwei Jiao
Histone cell cycle regulator (HIRA) is a histone chaperone and has been identified as an epigenetic regulator. Subsequent studies have provided evidence that HIRA plays key roles in embryonic development, but its function during early neurogenesis remains unknown. Here, we demonstrate that HIRA is enriched in neural progenitor cells, and HIRA knockdown reduces neural progenitor cell proliferation, increases terminal mitosis and cell cycle exit, and ultimately results in premature neuronal differentiation. Additionally, we demonstrate that HIRA enhances β-catenin expression by recruiting H3K4 trimethyltransferase Setd1A, which increases H3K4me3 levels and heightens the promoter activity of β-catenin...
May 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28507606/transcription-and-chromatin-determinants-of-de-novo-dna-methylation-timing-in-oocytes
#16
Lenka Gahurova, Shin-Ichi Tomizawa, Sébastien A Smallwood, Kathleen R Stewart-Morgan, Heba Saadeh, Jeesun Kim, Simon R Andrews, Taiping Chen, Gavin Kelsey
BACKGROUND: Gametogenesis in mammals entails profound re-patterning of the epigenome. In the female germline, DNA methylation is acquired late in oogenesis from an essentially unmethylated baseline and is established largely as a consequence of transcription events. Molecular and functional studies have shown that imprinted genes become methylated at different times during oocyte growth; however, little is known about the kinetics of methylation gain genome wide and the reasons for asynchrony in methylation at imprinted loci...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28484589/idh1-or-2-mutations-do-not-predict-outcome-and-do-not-cause-loss-of-5-hydroxymethylcytosine-or-altered-histone-modifications-in-central-chondrosarcomas
#17
Arjen H G Cleven, Johnny Suijker, Georgios Agrogiannis, Inge H Briaire-de Bruijn, Norma Frizzell, Attje S Hoekstra, Pauline M Wijers-Koster, Anne-Marie Cleton-Jansen, Judith V M G Bovée
BACKGROUND: Mutations in isocitrate dehydrogenase (IDH)1 or -2 are found in ~50% of conventional central chondrosarcomas and in up to 87% of their assumed benign precursors enchondromas. The mutant enzyme acquires the activity to convert α-ketoglutarate into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which competitively inhibits α-ketoglutarate dependent enzymes such as histone- and DNA demethylases. METHODS: We therefore evaluated the effect of IDH1 or -2 mutations on histone modifications (H3K4me3, H3K9me3 and H3K27me3), chromatin remodeler ATRX expression, DNA modifications (5-hmC and 5-mC), and TET1 subcellular localization in a genotyped cohort (IDH, succinate dehydrogenase (SDH) and fumarate hydratase (FH)) of enchondromas and central chondrosarcomas (n = 101) using immunohistochemistry...
2017: Clinical Sarcoma Research
https://www.readbyqxmd.com/read/28484075/twist1-wdr5-hottip-regulates-hoxa9-chromatin-to-facilitate-prostate-cancer-metastasis
#18
Reem Malek, Rajendra P Gajula, Russell D Williams, Belinda Nghiem, Brian W Simons, Katriana Nugent, Hailun Wang, Kekoa Taparra, Ghali Lemtiri-Chlieh, Arum R Yoon, Lawrence True, Steven S An, Theodore L DeWeese, Ashley E Ross, Edward M Schaeffer, Kenneth J Pienta, Paula J Hurley, Colm Morrissey, Phuoc T Tran
TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development...
May 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28483910/rna-binding-by-the-histone-methyltransferases-set1-and-set2
#19
Camille Sayou, Gonzalo Millán-Zambrano, Helena Santos-Rosa, Elisabeth Petfalski, Samuel Robson, Jonathan Houseley, Tony Kouzarides, David Tollervey
Histone methylation at H3K4 and H3K36 is commonly associated with genes actively transcribed by RNA polymerase II (RNAPII) and is catalyzed by yeast Set1 and Set2, respectively. Here we report that both methyltransferases can be UV-crosslinked to RNA in vivo. High-throughput sequencing of the bound RNAs revealed strong Set1 enrichment near the transcription start site, whereas Set2 was distributed along pre-mRNAs. A subset of transcripts showed notably high enrichment for Set1 or Set2 binding relative to RNAPII, suggesting functional post-transcriptional interactions...
May 8, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#20
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
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