chromatin remodeling



In the nucleus of eukaryotic cells, DNA is highly compacted and organized into a condensed structure, called chromatin, by both histone and nonhistone proteins.  There are two distinct functional forms of chromatin:
1. Heterochromatin–is condensed and highly repressive.
2. Euchromatin–is relaxed and generally conducive for transcription.
The nucleosome is:
1. The basic unit of the chromatin
2. Formed of 147 base pairs of DNA wrapped 1.6 times around an octamer composed of two H3-H4 histone dimers which are joined together as a stable tetramer and flanked by two separate H2A-H2B dimers.
3. Histone H1 acts as a linker, and together with other proteins (non-histone), allows for a high order of chromatin organization and compaction.
4. These core histone molecules are highly conserved.

All ATP-dependent chromatin-remodelling machineries that have been identified so far are multi-protein complexes containing a catalytic subunit that is part of the SWI2/SNF2 superfamily of ATPases. There are four different classes of chromatin-remodelling complexes within this superfamily — SWI/SNF, ISWI, CHD and INO80. The classification of chromatin-remodelling complexes is based on the presence of motifs outside the ATPase region. SWI/SNF members contain a BROMODOMAIN, ISWI members a SANT DOMAIN and CHD members a CHROMODOMAIN and a DNA-binding domain. Members of the INO80 class do not contain any of these domains; instead, their ATPase domain contains an insert that splits it into two segments.

The process of chromatin remodelling generally refers to various changes in chromatin, all of which involve changes in the DNA–histone interaction within nucleosomes. Biochemical studies have shown that chromatin-remodelling complexes use the energy from ATP hydrolysis to induce these changes. They include the mobilization and repositioning of histone octamers in cis (along the same DNA template molecule) and in trans (from one DNA template molecule to another one), the loss of superhelical torsion of nucleosomal DNA, and the increase in accessibility to nucleosomal DNA for nucleases or proteins involved in transcription. Interestingly, recent studies have shown that ATP-dependent chromatin remodelling also provides a means to change the histone composition of a nucleosome. The yeast SWR1 complex, a member of the INO80 class of remodellers, associates with Htz1, a homologue of the mammalian H2A variant H2AZ. This complex can drive the ATP-dependent replacement of H2A–H2B dimers with Htz1–H2B dimers in vitro. In vivo, SWR1 catalyses the incorporation of Htz1 into chromatin, which prevents the spreading of heterochromatin regions into regions of EUCHROMATIN.

Clearly the complex compacted state of DNA and its interaction with the histone proteins must be "remodeled" to allow interactions of the transcription factors and RNA polymerase (which is about the same size as a nucleosome). The regulation of this chromatin remodeling clearly affects gene transcription, and is another example of epigenetic changes that can affects phenotype. The state of chromatin structure is regulated by enzymes that affect histone structure and function by chemically modifying the histone proteins (through acetylation, methylation, and phosphorylation). Likewise, the DNA at the promoter region is changed by enzymes that remodel the DNA through an ATP dependent series of modifications. For example when histones are modified by histone acetyltransferase (HAT's), other modeling factors (SWI/SNF) are recruited to the chromatin. Chromatin remodeling would also be affected by that cell cycle stage of the cell.  For example, chromatin condensed in sister chromatids ready for cells division would have different remodeling requirements for gene transcription than might chromatin in the form of bead on a string. Likewise remodeling efforts would also be gene-specific.

Chromosomal breaks destabilize the genome and can cause developmental defects and diseases such as cancer.  Alternations in chromatin remodeling could also lead to changes in gene expression. SNF5 is a component of the SWI/SNF complex and in its normal form acts to suppress tumors (i.e. its gene is a tumor suppressor gene).  Mutations in SNF5 are associated with rare and aggressive childhood tumors.

DNA double-strand breaks (DSBs) arise through both replication errors and from exogenous events such as exposure to ionizing radiation. DSBs are potentially lethal, and cells have evolved a highly conserved mechanism to detect and repair these lesions. This mechanism involves phosphorylation of histone H2AX (γH2AX) and the loading of DNA repair proteins onto the chromatin adjacent to the DSB. It is now clear that the chromatin architecture in the region surrounding the DSB has a critical impact on the ability of cells to mount an effective DNA damage response. DSBs promote the direct the formation of open, relaxed chromatin domains which are spatially confined to the area surrounding the break. These relaxed chromatin structures are created through the coupled action of the p400 SWI/SNF ATPase and histone acetylation by the Tip60 acetyltransferase. The resulting destabilization of nucleosomes at the DSB by Tip60 and p400 is required for ubiquitination of the chromatin by the RNF8 ubiquitin ligase, and for the subsequent recruitment of the brca1 complex. Chromatin dynamics at DSBs can therefore exert a powerful influence on the process of DSB repair. Further, there is emerging evidence that the different chromatin structures in the cell, such as heterochromatin and euchromatin, utilize distinct remodeling complexes and pathways to facilitate DSB. The processing and repair of DSB is therefore critically influenced by the nuclear architecture in which the lesion arises.

ChromatinDB Chromatin Database
HHMD Human Histone Modification Database
NHGRI Histone Database
MethyCancer database of human DNA Methylation and Cancer

chromatin organization


ORTHOLOGY CLASS Homo sapiens L. (human) [HSA] Mus musculus L. (mouse) [MMU] Caenorhabditis elegans Maupas (nematode) [CEL] Drosophila melanogaster Meigen (fruit fly) [DME] Saccharomyces cerevisiae Meyen ex E.C. Hansen (budding yeast) [SCE] Schizo-saccharomyces pombe Lindner (fission yeast) [SPO] Escherichia coli Migula (bacterium) K-12 MG1655 [ECO] Arabidopsis thaliana (L.) Heynh. (mouse-ear cress) [ATH]
ko:K11653 (AT-rich interactive domain-containing protein 1) ARID1B
let-526 osa
ko:K14440 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 [EC:]) SMARCAL1 Smarcal1 SMARCAL1-like Marcal1 CHR18
ko:K14439 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 [EC:]) SMARCAD1 Smarcad1 M03C11.8 Etl1 FUN30 fft2 ETL1
ko:K11684 (bromodomain-containing factor 1) BDF2
ko:K11683 (SWR1-complex protein 7) SWC7
ko:K11682 (SWR1-complex protein 3) SWC3
ko:K11681 (helicase SWR1 [EC:]) SWR1 swr1
ko:K11786 (ATP-dependent helicase STH1/SNF2 [EC:3.6.4.-]) STH1
ko:K11776 (SWI/SNF complex component SWP82) SWP82
ko:K11775 (SWI/SNF complex component SWP73) SNF12
ko:K11774 (SWI/SNF complex component SNF11) SNF11
ko:K11773 (SWI/SNF complex component SNF6) SNF6
ko:K11772 (SWI/SNF complex subunit SWI3) SWI3
ko:K11771 (SWI/SNF chromatin-remodeling complex subunit SWI1) SWI1 sol1
ko:K11770 (chromatin structure-remodeling complex subunit SFH1) SFH1 sfh1
ko:K11769 (chromatin structure-remodeling complex protein HTL1) HTL1
ko:K11768 (actin-related protein 9) ARP9 arp9
ko:K11767 (actin-related protein 7) ARP7
ko:K11766 (chromatin structure-remodeling complex subunit RSC58) RSC58 rsc58
ko:K11764 (chromatin structure-remodeling complex protein RSC14) LDB7
ko:K11763 (chromatin structure-remodeling complex subunit RSC9) RSC9 rsc9
ko:K11762 (chromatin structure-remodeling complex subunit RSC8) RSC8
ko:K11761 (chromatin structure-remodeling complex protein RSC7) NPL6 snf59
ko:K11760 (chromatin structure-remodeling complex subunit RSC6) RSC6
ko:K11759 (chromatin structure-remodeling complex subunit RSC4) RSC4 rsc4
ko:K11758 (chromatin structure-remodeling complex subunit RSC3/30) RSC30
ko:K11756 (chromatin structure-remodeling complex subunit RSC1/2) RSC2
ko:K11400 (actin-related protein 4) ARP4 arp42
ko:K11680 (non-histone protein 10) NHP10
ko:K11679 (Ino eighty subunit 5) IES5
ko:K11678 (Ino eighty subunit 4) IES4
ko:K11677 (Ino eighty subunit 3) IES3
ko:K11676 (Ino eighty subunit 2) IES2 ies2
ko:K11675 (Ino eighty subunit 1) IES1
ko:K11674 (microspherule protein 1) MCRS1 Mcrs1 H28O16.2 Rcd5
ko:K11673 (actin-related protein 8) ACTR8 Actr8 Arp8 ARP8 arp8 ATARP9
ko:K11672 (actin-related protein 5) ACTR5 Actr5 Arp5 ARP5 arp5 ATARP5
ko:K11671 (nuclear factor related to kappa-B-binding protein) NFRKB Nfrkb Dmel_CG11970
ko:K11670 (TCF3 fusion partner) TFPT Tfpt
ko:K11669 (INO80 complex subunit E) INO80E Ino80e AT13868p
ko:K11668 (INO80 complex subunit D) INO80D Ino80d
ko:K11667 (INO80 complex subunit C) INO80C Ino80c CG12659 IES6 ies6 INO80 complex subunit C
ko:K11666 (INO80 complex subunit B) INO80B Ino80b CG10395
ko:K11665 (DNA helicase INO80 [EC:]) INO80 Ino80 Ino80 INO80 ino80 INO80
ko:K11664 (vacuolar protein sorting-associated protein 72) VPS72 Vps72 C17E4.6 YL-1 VPS72 swc2 SWC2
ko:K11663 (zinc finger HIT domain-containing protein 1) ZNHIT1 Znhit1 CD4.7 Dmel_CG31917 VPS71 vps71 SEF
ko:K11341 (YEATS domain-containing protein 4) YEATS4 Yeats4 gfl-1 Gas41 YAF9 yaf9 GAS41
ko:K11324 (DNA methyltransferase 1-associated protein 1) DMAP1 Dmap1 ekl-4 DMAP1 SWC4 swc4 At2g47210
ko:K11338 (RuvB-like protein 2 [EC:]) RUVBL2 Ruvbl2 RUVB (ruvb-2) rept RVB2 rvb2 At5g67630
ko:K04499 (RuvB-like protein 1 (pontin 52)) RUVBL1 Ruvbl1 Ruvb-1 pont RVB1 rvb1 RIN1
ko:K11662 (actin-related protein 6) ACTR6 Actr6 Actr13E ARP6 arp6 ATARP6
ko:K11661 (helicase SRCAP [EC:3.6.4.-]) SRCAP Srcap
ko:K11726 (nucleosome-remodeling factor 38 kDa subunit [EC:]) Nurf-38
ko:K11728 (nucleosome-remodeling factor subunit BPTF) BPTF Bptf nurf-1 E(bx)
ko:K11727 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 1 [EC:3.6.4.-]) SMARCA1 Smarca1
ko:K11591 (methyl-CpG-binding domain protein 3) MBD3 Mbd3
ko:K11660 (metastasis-associated protein MTA) MTA3
lin-40 MTA1-like
ko:K11659 (histone-binding protein RBBP7) RBBP7 Rbbp7
ko:K10752 (histone-binding protein RBBP4) RBBP4 Rbbp4 rba-1
Caf1 HAT2 pcf3
ko:K11643 (chromodomain-helicase-DNA-binding protein 4 [EC:]) CHD4 Chd4 let-418 Mi-2 PKL
ko:K11642 (chromodomain-helicase-DNA-binding protein 3 [EC:]) CHD3 Chd3
ko:K06067 (histone deacetylase 1/2 [EC:]) HDAC1
Rpd3 RPD3 clr6 hda17
ko:K11656 (chromatin accessibility complex protein 1) CHRAC1 Chrac1 Chrac-16
ko:K11654 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 [EC:3.6.4.-]) SMARCA5 (ISWI) Smarca5 isw-1 Iswi CHR11
ko:K11652 (actin-like protein 6B) ACTL6B Actl6b swsn-6 Bap55
ko:K11340 (actin-like protein 6A) ACTL6A Actl6a
ko:K05692 (actin beta/gamma 1) ACTB
ACT1 act1
ko:K11651 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E, member 1) SMARCE1 Smarce1 swsn-3 dalao
ko:K11650 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D) SMARCD1
Bap60 ssr3 At3g01890
ko:K11649 (SWI/SNF related-matrix-associated actin-dependent regulator of chromatin subfamily C) SMARCC2
psa-1 mor ssr2
ko:K11648 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) SMARCB1 (SNF5) Smarcb1 snfc-5 Snr1 SNF5 snf5 BSH
ko:K11647 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2/4 [EC:3.6.4.-]) SMARCA2
brm At5g19310


  • SWI/SNF nucleosome remodellers and cancer.

    , , : [PUBMED]
  • The SWI/SNF complex and cancer.

    , , : [PUBMED]
  • Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer.

    , , : [PUBMED]
  • Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex.

    , , : [PUBMED]
  • Loss of SNF5 expression correlates with poor patient survival in melanoma.

    , , : [PUBMED]
  • Crosstalk between histone modifications during the DNA damage response.

    , , : [PUBMED]
  • Chromatin dynamics and the repair of DNA double strand breaks.

    , , : [PUBMED]
  • The histone deacetylase-3 complex contains nuclear receptor corepressors.
    Wen YD., Perissi V., Staszewski LM., Yang WM., Krones A., Glass CK., Rosenfeld MG., Seto E.
    Proc. Natl. Acad. Sci. U.S.A., 2000 Jun, 97:7202-7 [PUBMED]
  • 2. Chromatin assembly with H3 histones: full throttle down multiple pathways.

    , , : [PUBMED]
  • A structural perspective on the where, how, why, and what of nucleosome positioning.

    , , : [PUBMED]
  • What controls nucleosome positions?

    , , : [PUBMED]
  • The linker-protein network: control of nucleosomal DNA accessibility.

    , , : [PUBMED]
  • Regulation of DNA replication by chromatin structures: accessibility and recruitment.

    , , : [PUBMED]
  • Determinants and dynamics of genome accessibility.

    , , : [PUBMED]
  • Chromatin remodelling: the industrial revolution of DNA around histones.

    , , : [PUBMED]
  • Chromatin and the DNA damage response: The cancer connection.

    , , : [PUBMED]
  • The Nucleosome Remodeling Factor.

    , , : [PUBMED]

Last modification date: Oct. 11, 2011