DOCSLIB.ORG

4 Transcription Part

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
4 Transcription Part Transcripon factors Once associated with the promoter, what do transcripon factors do? u Interact with/recruit the core transcriponal machinery u Recruit chroma)n-modifying ac)vi)es Transcripon factors Once associated with the promoter, what do transcripon factors do? u Interact with/recruit the core transcriponal machinery v Co-acvators Ac)vate transcrip)on but do not bind DNA v Mediator Mul)subunit complex that “mediates” between transcripon factors/coacvators and the core transcrip)on machinery (TFII family factors, RNA polymerase II) Transcripon factors Once associated with the promoter, what do transcripon factors do? u Interact with/recruit the core transcriponal machinery u Recruit chroma)n-modifying ac)vi)es v Nucleosome remodeling v Acetylases/deacetylases v Methylases/demethylases Black – DNA Blue – H3 Green – H4 Space-filling model of a core nucleosome Blue – protein Orange - DNA Nucleosome posioning around transcripon start sites is not random DNA accessibility is important for promoter func)on, this requires that nucleosomes be re-posioned (“remodeled”) during transcripon iniaon Types of Histone Modifica)ons Taken from h,ps://www.plant-epigenome.org/category/lecture-topic/histone-modificaons h,ps://www.plant-epigenome.org/teaching-tools Types of Histone Modifica)ons phosphorylaon acetylaon ubiquinaon methylaon Bhaumik, Smith, and Shilafard, 2007. Features of Histone Modifica)ons • Covalently aached groups (usually to histone tails) Methyl Acetyl Phospho Ubiqui=n SUMO • Reversible and Dynamic – Enzymes that add/remove modificaon – Signals • Have diverse biological func=ons Cell, 111:285-91, Nov. 1, 2002 " Features of Histone Modifica)ons •! Small vs. Large groups Ub = ~8.5 kDa •! One or up to three groups per residue H4 = 14 kDa Jason L J M et al. J. Biol. Chem. 2005 Histone Modifica)ons and Modifers •! Writers: enzymes that add a mark •! Readers: proteins that bind to and “interpret” the mark •! Erasers: enzymes that remove a mark Tarakhovsky, A., Nature Immunology, 2010. Roles of Acetyla)on 1. Opens up chroman: –! Reduces charge interac=ons of histones with DNA (K has a posi=ve charge) –! Prevents chroman compac=on (H4K16ac prevents 30nm fiber formaon) Robinson et al., J. Mol. Biol., 2008. 2. Recruits chroma)n proteins with bromodomains (SWI/SNF, HATs: GCN5, p300) PCAF 3. May occur at same residues as methylaon with repressive effect (compeve antagonism) H3K27ac H3K27me3 Mujtaba et al., Oncogene, 2007. Yang and Chen, Cell Research, 2011. Roles of Lysine methylation" Roles of Lysine Methyla)on 1. Recruitment of other chroma)n proteins through specific domains: Chromodomain (CHD ATPases, HP1, PC) Chromo-like Tudor (some histone demethylases) (Royal) PhD (many chroman regulators BPTF, ING2) MBT (in some polycomb proteins) WD-40 (WDR5) Roles of Lysine Methyla)on 2. Different readout depending on level of methylaon –! Methylaon status of H3K4 is recognized by different domains •! H3K4me1: chromodomain in CHD1 (ATPase) = transcrip=on ac=vaon •! H3K4me2: WD-40 domain in WDR5 in MLL (Trx) = transcrip=on ac=vaon •! H3K4me3: PhD domain of BPTF in NURF (ISWI) = transcrip=on ac=vaon •! H3K4me3: PhD ING2 recognizes during DNA damage and shuts down ac=ve transcrip=on through mSin3a-HDAC1 Promoters Enhancers Heintzman N et al., Nature Gene=cs, 2007. Roles of Lysine Methyla)on 3. Transcriponal ac)vaon –! H3K4me3: euchroman promoter, 5’ end ac=vates transcrip=on (Set1) –! H3K36me3: in gene (ORF), transcrip=onal elongaon (Set2) Li et al., Cell, 2007. Roles of Lysine Methyla)on 4. Transcriponal repression •! H3K9me (Suv39H1) •! In promoter, represses transcrip=on •! In larger domains, heterochroman formaon •! H3K27me (EZH2) •! Repression of transcrip=on •! Polycomb group silencing •! H4K20me (Suv420H1) •! Some forms of silencing and repression of gene expression •! In repe==ve elements, similar localizaon as H3K9me3 in ES cells Li et al., Cell, 2007. Histone Ubiquinaon •! Ubiqui=naon –! H2A K119: •! Func=on: Polycomb repression (Ring1a, PCG) –! H2B K123: ac=vaon (Rad6+Bre yeast; RNF20/RNF40 and UbcH6 in mam) •! Func=on: FACT recruitment, transcrip=onal elongaon –! H3 and H4: DNA repair (CUL4) •! De-ubiqui=naon –! H2A: Dub (PCAF) •! Func=on: counteract Polycomb –! H2B: Ubp8 (SAGA) •! Func=on: transcrip=on elongaon Different histone modifications are associated with different parts of the gene Chromatin and DNA methylation define chromosome domains Different histone modificaons are recognized by different families of proteins – histone H3 as an example These proteins provide connecons to downstream partners/events, and perhaps also to upstream signaling cascades ANRV413-BI79-06 ARI 27 April 2010 21:50 JARID/ LSD1/ JMJD1/ JMJD2/ JMJD3/ FBXL/ KDM5 KDM1 KDM3 KDM4 UTX/KDM6 KDM2 4 K Q T T A R G R T G 36 A 9 A V H3 K K S P A K T 27 S G K P G R H K A A A K K I P R T H R K Q L A R 20 K A Promoter or activation G G Heterochromatin or repression K G Elongation L G Enhancer K G DNA damage G H4 S G R G K Figure 3 Substrate specificity of histone demethylases described to date. Dashed lines point to the methylated residue(s) that are demethylated by the indicated enzymes. The embedded numbers refer to the methylated amino acid residue on each histone. The general function of each mono-, di-, and trimethylation state is depicted in dots of distinct colors as shown in the figure key. Abbreviations: JARID, Jumonji and ARID domain protein (also known as KDM5); LSD1, Lysine-specific demethylase, also known as KDM1A; JMJD1, Jumonji domain protein 1, also known as KDM3; JMJD2, Jumonji domain protein 2, also known as KDM4; UTX, Ubiquitously transcribed tetratricopeptide repeat, X chromosome protein, also known as KDM6A; JMJD3, Jumonji domain protein 3, also known as KDM6B; FBXL, F-box and leucine-rich repeat protein, also known as KDM2. Recent structural efforts have provided sig- globular halves of the amine oxidase active site. nificant insights into some of these issues, as This so-called tower domain serves as the bind- by University of Kentucky on 08/16/10. For personal use only. discussed below. ing interface between LSD1 and its protein co- factor, CoREST,and distinguishes it from other amine oxidases (75, 76). Although nucleosomal LSD1-Mediated Demethylation substrates are refractory to recombinant LSD1, Annu. Rev. Biochem. 2010.79:155-179. Downloaded from arjournals.annualreviews.org and Chemical Inhibitors addition of recombinant CoREST endows nu- Analysis of the LSD1 structure has led to signif- cleosomal demethylation by LSD1, indicating icantly greater insight into its function. Over- that the primary function of CoREST is to en- all, the structure of LSD1 consists of an N- able LSD1 demethylation of nucleosomal sub- terminal SWIRM domain (74), and an amine strates (77, 78). Consistently, mutations that oxidase domain split into two halves, consist- inhibit the ability of CoREST to bind to DNA ing of a substrate-binding half and an FAD- inhibit the ability of the complex to demethy- binding half, which come together to form a late nucleosomes (76). globular domain (Figure 4a) (75, 76). The How does LSD1 achieve specificity for active site of the enzyme is located in be- H3K4me2/me1? According to these structural tween these two halves. Two long, antiparal- studies, much of the specificity of LSD1 is lel α-helices divide and project away from the intrinsic to its enzymatic pocket. The amine www.annualreviews.org • Histone Demethylases 161 ANRV413-BI79-06 ARI 27 April 2010 21:50 abcATP Mi2 ADP + Pi Coactivator? HDAC LSD1 HDAC ? 1/2 LSD1 1/2 LSD1 BHC80 BRAF CoREST ? 35 PHD RbAp MTA MBD AR/ER LSD1-CoREST LSD1-NuRD LSD1-AR/ER de PTIP Ash2L Activation-associated methyl marks SUZ12 Repression-associated methyl marks EED MOF MLL Histone acetylation RBBP2 UTX EZH2 RbBP5 Add modification WDR5 Remove modification ActivatorActivator MLL-UTX PRC2-RBBP2 Figure 5 Key histone demethylase complexes and their activities described to date. Green and red circles represent activation- and repression- associated methyl marks, respectively, and green triangles represent histone acetylation. Solid green lines and dashed red lines represent enzymatic activities that add or remove specific modifications, respectively. (a) The lysine-specific demethylase 1 (LSD1)-corepressor of RE1-silencing transcription factor (CoREST) complex. (b) The LSD1-nucleosome remodeling and deacetylase (NuRD) complex. (c) The LSD1-nuclear hormone receptor (AR/ER) complex. (d ) The mixed-lineage leukemia (MLL) protein-ubiquitously transcribed tetratricopeptide repeat, X chromosome protein (UTX) complex. (e) The Polycomb repressive complex 2 (PRC2)-retinoblastoma- binding protein 2 (RBBP2) complex. Abbreviations: AR/ER, androgen receptor/estrogen receptor; Ash2L, absent, small, or homeotic like 2; BHC80, BRAF and histone deacetylase complex 80; EED, embryonic ectoderm development; EZH2, enhancer of zeste homolog 2; HDAC1-2, histone deacetylase 1-2; MBD, methyl-CpG-binding domain protein 2; Mi2, myositis autoantigen 2; by University of Kentucky on 08/16/10. For personal use only. MOF, males absent on first; MTA, metastasis associated; PTIP, PAX interacting protein; RbAp, retinoblastoma-associated protein; RbBP, retinoblastoma-binding protein; SUZ12, suppressor of zeste homolog 12; WDR5, WD repeat domain protein 5. activity of LSD1 can also be coupled to Although human LSD1 has a clear role in Annu. Rev. Biochem. 2010.79:155-179. Downloaded from arjournals.annualreviews.org chromatin-remodeling Swi/Snf type ATPases repression as an H3K4 demethylase, there is important for transcriptional repression also evidence that it functions as an activator (Figure 5b). In the NuRD complex, the when present in other complexes, thus playing metastasis-associated (MTA) proteins function opposing roles in different physiological con- in place of CoREST and play an analogous texts. LSD1 has been demonstrated to associate function to allow LSD1 demethylation of directly with androgen receptor (AR), and in nucleosomal substrates (102). Like CoREST, this molecular context, LSD1 can demethy- the MTA proteins each contain a SANT do- late H3K9me2/me1 but not H3K4me2/1 main, which serve as Myb-like DNA-binding (Figure 5c) (103).
Load more

Recommended publications
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
    [Show full text]
  • Download Download
    Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/)
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • The Vitamin D Receptor in Cancer
    Proceedings of the Nutrition Society (2008), 67, 115–127 doi:10.1017/S0029665108006964 g The Authors 2008 The Summer Meeting of the Nutrition Society, hosted by the Irish Section, was held at the University of Ulster, Coleraine on 16–19 July 2007 Symposium on ‘Diet and cancer’ The vitamin D receptor in cancer James Thorne1* and Moray J. Campbell1,2 1Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston B15 2TT, UK 2Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions.
    [Show full text]
  • Lysine Methylation Regulators Moonlighting Outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart
    Lysine Methylation Regulators Moonlighting outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart To cite this version: Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart. Lysine Methylation Regulators Moonlighting outside the Epigenome. Molecular Cell, Elsevier, 2019, 10.1016/j.molcel.2019.08.026. hal-02359890 HAL Id: hal-02359890 https://hal.archives-ouvertes.fr/hal-02359890 Submitted on 14 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Lysine methylation regulators moonlighting outside the epigenome Evan M. Cornett1, Laure Ferry2, Pierre-Antoine Defossez2, and Scott B. RothBart1* 1Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. 2Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013 Paris, France. *Correspondence: [email protected], 616-234-5367 ABSTRACT Landmark discoveries made nearly two decades ago identified known transcriptional regulators as histone lysine methyltransferases; since then the field of lysine methylation signaling has Been dominated By studies of how this small chemical posttranslational modification regulates gene expression and other chromatin-Based processes. However, recent advances in mass spectrometry-Based proteomics have revealed that histones are just a suBset of the thousands of eukaryotic proteins marked By lysine methylation.
    [Show full text]
  • Epigenetic Regulation of Development by Histone Lysine Methylation
    Heredity (2010) 105, 24–37 & 2010 Macmillan Publishers Limited All rights reserved 0018-067X/10 $32.00 www.nature.com/hdy REVIEW Epigenetic regulation of development by histone lysine methylation S Dambacher1, M Hahn1 and G Schotta Munich Center for Integrated Protein Science (CiPSM) and Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany Epigenetic mechanisms contribute to the establishment and (HMTases) and specific binding factors for most methylated maintenance of cell-type-specific gene expression patterns. lysine positions has provided a novel insight into the mechanisms In this review, we focus on the functions of histone lysine of epigenetic gene regulation. In addition, analyses of HMTase methylation in the context of epigenetic gene regulation during knockout mice show that histone lysine methylation has developmental transitions. Over the past few years, analysis of important functions for normal development. In this study, we histone lysine methylation in active and repressive nuclear review mechanisms of gene activation and repression by histone compartments and, more recently, genome-wide profiling of lysine methylation and discuss them in the context of the histone lysine methylation in different cell types have revealed developmental roles of HMTases. correlations between particular modifications and the transcrip- Heredity (2010) 105, 24–37; doi:10.1038/hdy.2010.49; tional status of genes. Identification of histone methyltransferases published online 5 May 2010 Keywords: epigenetics; histone lysine methylation; heterochromatin; mouse development Introduction Activation and repression are facilitated by Development is accomplished by spatial and temporal histone lysine methylation regulation of gene expression patterns. The identity of Major methylation sites on histones H3 and H4 are each cell type is maintained and passed on to daughter located in the tail (H3K4, H3K9, H3K27, H3K36 and cells by mechanisms that do not alter the DNA sequence H4K20) and the nucleosome core region (H3K79).
    [Show full text]
  • Integrated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Properties of Mesenchymal Stromal
    Integrated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Properties of Mesenchymal Stromal Cells Cédric Ménard, Joelle Dulong, David Roulois, Benjamin Hebraud, Léa Verdière, Céline Pangault, Vonick Sibut, Isabelle Bezier, Nadège Bescher, Céline Monvoisin, et al. To cite this version: Cédric Ménard, Joelle Dulong, David Roulois, Benjamin Hebraud, Léa Verdière, et al.. Inte- grated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Prop- erties of Mesenchymal Stromal Cells. STEM CELLS, AlphaMed Press, 2020, 38 (1), pp.146-159. 10.1002/stem.3077. hal-02282131 HAL Id: hal-02282131 https://hal-univ-rennes1.archives-ouvertes.fr/hal-02282131 Submitted on 10 Sep 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Stem Cells Integrated transcriptomic, phenotypic, and functional study reveals tissue-specific immune properties of mesenchymal stromal cells Journal: Stem Cells Manuscript ID Draft Wiley - Manuscript Type: Original Research Date Submitted by Forthe Peer Review n/a Author: Complete
    [Show full text]
  • Islet-1 Is Essential for Pancreatic Β-Cell Function Benjamin N. Ediger
    Page 1 of 68 Diabetes June 20, 2014 Diabetes Islet-1 is essential for pancreatic β-cell function Benjamin N. Ediger1,5, Aiping Du1, Jingxuan Liu1, Chad S. Hunter3, Erik R. Walp1, Jonathan Schug4, Klaus H. Kaestner4, Roland Stein3, Doris A. Stoffers5* and Catherine Lee May*,1,2 1Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA 4Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 5Department of Medicine and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA * These authors contributed equally. Running Title: Isl-1 regulates β-cell function Address correspondence to: Catherine Lee May, Ph.D. 3615 Civic Center Blvd, Room 516E Philadelphia, PA 19104 Phone: 267-426-0116 E-mail: [email protected] And Doris A. Stoffers, M.D., Ph.D. 3400 Civic Center Boulevard, 12-124 SCTR Philadelphia, PA 19104 Phone: (215) 573-5413 E-mail: [email protected] Fax: 215-590-3709 Word Count: 4065 Number of Tables: 6 (all are supplemental) Number of Figures: 9 (3 are supplemental) Diabetes Publish Ahead of Print, published online July 15, 2014 Diabetes Page 2 of 68 Abstract Isl-1 is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear.
    [Show full text]
  • The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes Via Histone Deacetylation Simon Weissmann1,2, Paul A
    Published OnlineFirst May 29, 2018; DOI: 10.1158/0008-5472.CAN-18-0342 Cancer Genome and Epigenome Research The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation Simon Weissmann1,2, Paul A. Cloos1,2, Simone Sidoli2,3, Ole N. Jensen2,3, Steven Pollard4, and Kristian Helin1,2,5 Abstract Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system can- Low MAPK signaling High MAPK signaling cers. CIC is a transcription factor that is mutated in most RTKs patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. MEK Analysis of the Drosophila melanogaster ortholog of ERK SIN3 CIC, Capicua, indicates that CIC loss phenocopies CIC HDAC activation of the EGFR/RAS/MAPK pathway, and HMG C-term studies in mammalian cells have demonstrated a role SIN3 CIC HDAC for CIC in repressing the transcription of the PEA3 HMG C-term Ac Ac subfamily of ETS transcription factors. Here, we address Ac Ac the mechanism by which CIC represses transcription and assess the functional consequences of CIC inacti- vation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched ETV, DUSP, CCND1/2, SHC3,... for MAPK effector genes involved in cell-cycle regulation Normal Astrocytoma and proliferation. CIC binding to target genes was Glioblastoma multiforme abolished by high MAPK activity, which led to their 1p/19q deletion CIC-Mutants transcriptional activation. CIC interacted with the SIN3 SIN3 deacetylation complex and, based on our results, we SIN3 CIC suggest that CIC functions as a transcriptional repressor HDAC HDAC HMG C-term through the recruitment of histone deacetylases.
    [Show full text]