Chromatin remodeling ATPases non-covalent change

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Chromatin remodeling ATPases non-covalent change. Lecture outline. Types of chromatin remodelers complexes protein domains Activities of chromatin remodelers on chromatin in the organism. Chromatin remodeling ATPases. txn assembly. DNA methylation. txn. exchange. txn repression. - PowerPoint PPT Presentation

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  • Chromatin remodeling

    ATPasesnon-covalent change

  • Lecture outlineTypes of chromatin remodelers

    complexes

    protein domains

    Activities of chromatin remodelers

    on chromatin

    in the organism

  • Chromatin remodeling ATPasestxn repressiontxntxnassemblyDNA methylationexchangerepairDNA methylationheterochromationrecombinationarchealTBP

  • ISWICHDSWI2/SNF2INO80/SWR1

  • ATPase domainClapier and Cairns Ann. Rev. Biochem. 2009

  • Activities of chromatin remodeling ATPases

  • Clapier and Cairns, Annu. Rev. Biochem. 2009 Chromatin assembly

  • Dynamic Range of Chromatin Structure Created by ATP-Dependent Chromatin RemodelingSlide courtesy of Dr. Hua-Ying Fan

  • Shared characteristics of chromatin remodeling complexes

    bind nucleosomes

    are DNA-dependent ATPases

    recognize histone modifications

    ATPase activity can be regulated

    interact with other proteins

    From Clapier and Cairns, Annu. Rev. Biochem. 2009

  • Assays for chromatin remodeling Non-covalent alteration!

  • sliding

  • Assays for chromatin remodeling Also MNAse qPCR or MNAse seq or MNAse H3 ChIP seq

  • Persistence

  • Proc. Natl. Acad. Sci. USAVol. 95, pp. 49474952, April 1998Perturbation of nucleosome core structure by the SWI/SNFcomplex persists after its detachment, enhancing subsequenttranscription factor bindingJACQUES COTE ,CRAIG L. PETERSON, AND JERRY L. WORKMAN cold competitor oligonucleosomes

  • one remodeler per nucleosome

    multiple enzymatic reactions destabilize 1 nucleosome

    14 histone-DNA contacts

    use ATP hydrolysis to break (ca. 1kcal/mol for each contact)

    ATPases bind near center of nucleosomes (2 turns from dyad)

    translocate along DNA 3 to 5

    generate DNA loops, reposition nucleosome or destabilize

    Chromatin remodeling

  • ISWI(SNF2H)

  • SMALL COMPLEXES (generally)Yadon and Tsukiyama Cell Snapshot 2011

  • SMALL COMPLEXES (generally)MANY COMPLEXESYadon and Tsukiyama

  • Roles of ISWI

    nucleosome array formationchromatin assembly, replication

    heterochromatin formation

    reprogramming (nuclear transfer)

    transcriptional regulationsome PolII, PolI

  • ISWI can position nucleosomes onto unfavorable DNA

  • ISWI: greenPolII: redISWI role in transcriptionDeuring et al., Molecular Cell, Vol. 5, 355365, February, 2000The ISWI Chromatin-Remodeling Protein Is Required for Gene Expression and the Maintenance of Higher Order Chromatin Structure In Vivo.

  • Female iswi mut.Male iswi mut.Deuring et al., Molecular Cell, Vol. 5, 355365, February, 2000The ISWI Chromatin-Remodeling Protein Is Required for Gene Expression and the Maintenance of Higher Order Chromatin Structure In Vivo.

    ISWI: required for condensation of male X

  • Role of the domains

  • Blue + chargeRed - chargeRole of the domains

  • Yamada et al., Nature 2011Role of the domains

  • SANT/HAND domain contacts histone tails- charge: histone tail interaction+ charge: DNA interaction

    Slide domain linker DNA contact, measures distanceequal spacing of nucleosomes

    ATPase domainnear dyad, motor, translocationROLE of ISWI domains

  • Loop propagation modelsYamada et al., Nature 2011

  • SWI/SNF

  • Isolated as sucrose-non-fermenting mutants in yeastsnf2, snf5, snf6

    Isolated as mating type switch deficient mutants in yeastswi1, swi2, swi3

    SNF2=SWI2

    SWI2/SNF2 subfamily of chromatin-remodeling ATPases

  • LARGE COMPLEXES (generally)Ca. 11 subunits, 2 MD in sizeCasten et al., Cell snapshot 2011

  • Core complex ATPase Snf2 (BRM/BRG1)Snf5 (BAF47)Swi3 (BAF155/BAF170)

    Function of some subunits not yet understoodATPase and core: sufficient in vitro, other subunits required in vivoother subunitsSwp73 or BAF60 actin related proteins (ARP)BAF 57

    SWI2/SNF2 complexes

  • Trends in Genetics 2007Two types of complexes in most organismsa,ba,b

  • Clapier and Cairns, Annu. Rev. Biochem. 2009

  • Ho and Crabtree Nature 2010

  • BROMO domainbinds acetylated lysines on histone tailsHSA domain protein interactionsactin/ARP transcription factors

    ATPase domainnear dyad, motor, translocationROLE of SNF2/BRM domains

  • ROLE of SNF2/BRM domainsNew SnAC domain required for remodeling activitySen et al., NAR 2011Hopfner et al. COSB 2012

  • SNF2 ATPase activity

    change nucleosome positionincreased regulatory protein access!

    change nucleosome conformation

    eject histone octamer

    displace H2A/H2B dimer

  • Roles of SWI2/SNF2

    Inducible gene expression:transcription initiationtranscription elongation

    Splicing

    Repair

    Roles in development and stress responses

  • slidingATP-dependentChromatin Remodeling ComplexCis-regulatory elementActivation or repression!

  • slidingATP-dependentChromatin Remodeling ComplexCis-regulatory elementActivation or repression!

  • Only a subset of genes depends on SWI2/SNF2Holstege et al. (1998) Cell 95Whole genome expression analysis in S. cerevisiae

  • Role in activation and repression of transcription

    Regulation of select genesSWI2/SNF2 activities

  • Proc. Natl. Acad. Sci. USAVol. 95, pp. 49474952, April 1998Perturbation of nucleosome core structure by the SWI/SNFcomplex persists after its detachment, enhancing subsequenttranscription factor bindingJACQUES COTE ,CRAIG L. PETERSON, AND JERRY L. WORKMAN cold competitor oligonucleosomes

  • Zhang et al. The 2MD SWI/SNF complex fits around the entire nucleosome

  • Nature Structural & Molecular Biology 15, 1272 - 1277 (2008) Published online: 23 November 2008http://www.nature.com/nsmb/journal/v15/n12/extref/nsmb.1524-S5.mov

  • RSC docks onto nucleosome1 = ATPase

  • Casten et al., Cell snapshot 2011

  • Liu et al., MCB2011

  • CHD ATPasesCHD1: role in chromatin assembly; open chromatinin pluripotent cells

    CHD3, 4HDAC complex subunits!NuRD complexalso contains Me-DNA binding protein (MBD2)complex connects deacetylation, chromatin remodeling and DNA methylation; repressive function

    CHD7: together with PBAF; CHARGE syndrome

    Together with SNF2: role in transcriptional elongation

  • Sims and Wade, Cell Snapshot 2011

  • Hopfner et al. COSB 2012Sharma et al. JBC 2011New insight into domains from crystal structure

  • CHROMO and PHD domainsbind methylated lysines on histone tailsmodulate activity of remodelers

    ATPase domainnear dyad, motor, translocationROLE of CHD ATPase domains

  • Hauk et al. Molec. Cell 2010Chromodomains gate CHD1 activity

  • Role in chromatin assemblyLusser et al., Nature Struc Mol Biol 2005CHRHC

  • INO80chromatin assemblyDNA repairinteracts with phosphorylated H2A.X (gammaH2A.X)transcriptionexchange H2A.Z with H2A

    SWR1H2A exchange with H2A.ZBoundary to heterochromatin spreadingtranscriptionally poised promoters (together with H3.3)

  • Bao and Shen Cell Snapshot 2011INO80/ SWR1ATPase domain

  • Morrison and Shen, Nature reviews Mol Cell Biol, 2009 Role of INO80 complex

  • Biochem. Cell Biol vol 84 2006Role of SWR complex

  • Instability of H2AZ allows high temperature to turn on genes in plants

  • Role of SWI2/SNF2

    ATPases in the organism

  • Role of chromatin remodeling ATPasesin cancer

    SWI2/SNF2 subgroup

    *mouse BRG1 mutants develop tumors at high frequency (non-small lung carcinoma)Biallelic loss observed in prostrate, lung, breast and pancreatic cancer cell lines

    *subunit hSNF5 (INI1) is tumor suppressorLOH in nearly all cases of pediatric rhabdoid sarcomarecapitulated in mouse models (conditional inactivationleas to lymphomas with 100% penentrance)

  • Role of chromatin remodeling ATPasesin cancer

    Others

    *dNURF: ISWI and p301 involved in neoplastic transformation *NURD: CHD1/MI2 linked to certain breast cancers

  • Role in other diseases

    * X-linked mental retardation*William syndrome

    *Cockayne syndrome

    *Schimke immuno-osseous dysplasia

  • Why are they so important?Maintenance and alteration of nucleosome

    occupancy and positioning

  • Useful terminology

  • Specificity of chromatin remodelers

    a. recruitment

  • ATP-DEPENDENT NUCLEOSOME REMODELINGPeter B. Becker and Wolfram HrzAnnu. Rev. Biochem. 2002. 71:24773

    CRM; chromatin remodelerTranscription factorMethyl -lysinePolymeraseAcetyl-LysineH3K14ac-RSCH3K4me-ISWINuclear hormone receptors-Brg1Gal1promoter SNF2H3K16 non ac - ISWI

  • Targeting of SWI/SNF

    no DNA binding specificity

    recruited by transcription factors in many organisms

    yeast: SWI5, GCN4, GAL4, VP16Drosophila: Ikaros, hunchback, tramtrackhuman: EKLF, C/EBPB, GR, MyoDplants: LFY, TCP, MP

  • Regulation of SWI2/SNF2 activity

    1. Post-translational modifications phosphorylation, acetylation, de-ubiquitylation

    2. Complex compositionregulatory subunits (SWI5, Drososphila)tissue specific subunits (BAF60)3. Interaction with small moleculesphosphatidyl inositol

    Hogan and WeiszMutation Research 618 (2007) 41-51

  • Regulation by phosphorylation, acetylation

  • Clapier and Cairns, Ann. Rev. Biochem. 2009

  • Regulation of SWI2/SNF2 activity

    1. Post-translational modifications phosphorylation, acetylation, de-ubiquitylation

    2. Complex compositionregu

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