Towards the human cancer epigenome - A first draft of histone modifications

被引:118
作者
Fraga, MF [1 ]
Esteller, M [1 ]
机构
[1] CNIO, Canc Epigenet Lab, Madrid 28029, Spain
关键词
histones; acetylation; methylation; epigenome; epigenetics; histone acetyltransferases; histone methyltransferases;
D O I
10.4161/cc.4.10.2113
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The disruption of genomic DNA methylation patterns was the first epigenetic abnormality to be described in human cancer. This imbalance involves the promoter CpG island hypermethylation of tumor-suppressor genes, causing transcriptional repression, and global genomic hypomethylation, leading to chromosomal instability and reactivation of endoparasitic sequences. The relationship between DNA methylation and histone modifications was initially described in the context of the inactivation of female X chromosomes and of the demonstration of strong interactions between the DNA methylation machinery and chromatin modifiers. The repression of tumor-suppressor genes by promoter hypermethylation was also found to be associated with a specific histone modification index. However, this jigsaw was missing a piece: a global view of how the histone modification landscape was distorted in cancer cells. We have recently discovered this piece of the puzzle, demonstrating that the association between DNA methylation and histone modification aberrations in cancer also occurs at the global level. In human and mouse tumors, histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively. Most importantly, these alterations occur within the context of the repetitive DNA sequences that also become hypomethylated in transformed cells. The global alterations of histone acetylation status suggest novel pathways by which histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes. In this regard, we have shown how the generation of particular fusion proteins involving HATs in leukemias is associated with an erasure of the monoacetylated lysine 16-H4 marker, whilst the loss of trimethylation at lysine 20-H4 disrupts heterochromatic domains and may reduce the response to DNA damage of cancer cells.
引用
收藏
页码:1377 / 1381
页数:5
相关论文
共 33 条
  • [11] Epigenetic differences arise during the lifetime of monozygotic twins
    Fraga, MF
    Ballestar, E
    Paz, MF
    Ropero, S
    Setien, F
    Ballestart, ML
    Heine-Suñer, D
    Cigudosa, JC
    Urioste, M
    Benitez, J
    Boix-Chornet, M
    Sanchez-Aguilera, A
    Ling, C
    Carlsson, E
    Poulsen, P
    Vaag, A
    Stephan, Z
    Spector, TD
    Wu, YZ
    Plass, C
    Esteller, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (30) : 10604 - 10609
  • [12] Protein mass analysis of histones
    Galasinski, SC
    Resing, KA
    Ahn, NG
    [J]. METHODS, 2003, 31 (01) : 3 - 11
  • [13] Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin
    Gonzalo, S
    García-Cao, M
    Fraga, MF
    Schotta, G
    Peters, AHFM
    Cotter, SE
    Eguía, R
    Dean, DC
    Esteller, M
    Jenuwein, T
    Blasco, MA
    [J]. NATURE CELL BIOLOGY, 2005, 7 (04) : 420 - U52
  • [14] Histone H4 acetylation of euchromatin and heterochromatin is cell cycle dependent and correlated with replication rather than with transcription
    Jasencakova, Z
    Meister, A
    Walter, J
    Turner, BM
    Schubert, I
    [J]. PLANT CELL, 2000, 12 (11) : 2087 - 2100
  • [15] ANTIBODIES TO DEFINED HISTONE EPITOPES REVEAL VARIATIONS IN CHROMATIN CONFORMATION AND UNDERACETYLATION OF CENTRIC HETEROCHROMATIN IN HUMAN METAPHASE CHROMOSOMES
    JEPPESEN, P
    MITCHELL, A
    TURNER, B
    PERRY, P
    [J]. CHROMOSOMA, 1992, 101 (5-6) : 322 - 332
  • [16] THE INACTIVE X-CHROMOSOME IN FEMALE MAMMALS IS DISTINGUISHED BY A LACK OF HISTONE-H4 ACETYLATION, A CYTOGENETIC MARKER FOR GENE-EXPRESSION
    JEPPESEN, P
    TURNER, BM
    [J]. CELL, 1993, 74 (02) : 281 - 289
  • [17] Histone modification in constitutive heterochromatin versus unexpressed euchromatin in human cells
    Jiang, GC
    Yang, F
    Sanchez, C
    Ehrlich, M
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2004, 93 (02) : 286 - 300
  • [18] Distinctive patterns of histone H4 acetylation are associated with defined sequence elements within both heterochromatic and euchromatic regions of the human genome
    Johnson, CA
    O'Neill, LP
    Mitchell, A
    Turner, BM
    [J]. NUCLEIC ACIDS RESEARCH, 1998, 26 (04) : 994 - 1001
  • [19] Dynamic histone modifications mark sex chromosome inactivation and reactivation during mammalian spermatogenesis
    Khalil, AM
    Boyar, FZ
    Driscoll, DJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (47) : 16583 - 16587
  • [20] Histone acetylation and deacetylation in yeast
    Kurdistani, SK
    Grunstein, M
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (04) : 276 - 284