Page 36 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

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Encyclopedia of Physical Science and Technology EN002G-104 May 17, 2001 20:53

828 Chromatin Structure and Modification

is significantly less abundant). In fact, the bulk of CpG in the presence of ligand. In contrast, other NHRs, includ-
dinucleotides occur within short (ca. 100–500 base pairs) ing the retinoic acid receptor and the thyroid hormone
stretches of the genome designated “CpG” islands—these receptor, reside in the nucleus irrespective of hormone.
occur most commonly in the promoters of genes. In ad- Their residence in the nucleus is not a passive one—both
dition to this peculiar distribution, the cytosine within TR and RAR remain bound to target gene promoters in
CpG dinucleotides is frequently covalently modified with the absence of hormone and act as potent transcriptional
a methyl group on position 5 (to yield 5-methylcytosine, repressors. The exact mechanism whereby these proteins
5-mC). There is very strong evidence that DNA methy- effect repression remained elusive until work in 1995 from
lation is a mechanism for targeting the transcriptional D. Moore, R. Evans, and M. Rosenfeld identified two
repression machinery to particular DNA sequences: for large (ca. 270 kDa) related polypeptides called N-CoR and
example, in our genomes, the bulk of genomic parasites SMRT. Subsequent work from these labs, and also those of
(i.e., transposons and retroviruses) are kept transcription- M. Lazar and A. Wolffe revealed unliganded TR and RAR
ally quiescent by methylation. Experiments indicate that can associate with HDAC via these corepressors, and that
the demethylation of repetitive DNA can have severe con- HDAC inhibitors will impair the repressive action by these
sequences for genomic stability: for example, retroele- regulators (the actual enzyme recruited by these proteins
ments begin uncontrolled proliferation in the genomes of is HDAC3). Whether the targeting of HDAC leads to chro-
interspecific hybrids in wallabies, and mutations in the matin deacetylation of any vertebrate genes is not known.
enzyme that effects DNA methylation (DNA methyltrans- In budding yeast, work from the laboratories of M. Grun-
ferase) in humans leads to marked chromosome instability stein and K. Struhl showed (via the application of ChIP)
due to pericentric heterochromatin expansion (this genetic that the transcriptional repressor Ume6p acts to silence
disorder—ICFsyndrome—ischaracterizedbyskeletalab- target genes via the recruitment of the HDAC Rpd3p, and
normalities and mental retardation). In addition, a very that such recruitment leads to histone tail deacetylation
common feature of neoplasia in humans is the aberrant over target gene promoters.
silencing of genes required for cell cycle arrest (such as The action of HDACs transcriptional repression path-
genes for cyclin-dependent kinase inhibitors); this is ef- waysisnotanacademicissue,sinceHDACinhibitorshave
fected by hypermethylating the CpG islands in the pro- long been known to be very potent cytostatic and differ-
moters of these genes. entiating agents. Thus, for example, a number of cell lines
A functional connection between DNA methylation and of cancerous origin can be driven to cease proliferation
the targeting of histone deacetylase emerged from stud- via the application of such HDAC inhibitors as tricho-
ies on transcriptional regulators discovered in A. Bird’s statin A or sodium butyrate. In addition, oncoproteins that
lab that bind methylated DNA selectively (i.e., these pro- are produced as a result of chromosomal translocations
teins bind 5mCpG but do not bind CpG) and appear to be in leukemias are known to depend on HDAC targeting
transcriptional repressors. Subsequent biochemical anal- for action; compounds that force a release of HDAC from
ysis in A. Bird and A. Wolffe’s lab revealed that one these chimeric proteins are successfully used in clinical
such protein—MeCP2—associates with histone deacety- practice to treat certain forms of leukemia.
lase and that an HDAC inhibitor prevents transcriptional An interesting property of HDACs is their tendency to
repression driven by MeCP2. These observations illumi- occur in large, multisubunit complexes. For example, as
nated the fact that hypermethylated DNA sequences re- originally discovered in the laboratory of A. Wolffe, and
side in deacetylated chromatin in vivo: thus, a simple subsequently by the laboratories of S. Schreiber and D.
model emerges according to which methylated DNA re- Reinberg, the predominant biochemical form of HDAC1
cruits specific proteins that recognize it selectively, and in our cells is the Mi-2/NRD complex; its most distin-
target HDAC to remodel chromatin adjacent to their bind- guishing feature is that it contains a histone deacetylase,
ing site into a repressive, deacetylated conformation. The a SWI/SNF family ATPase, and a protein that can selec-
profound relevance of this pathway to genomic control in tively bind to methylated DNA. An understanding of the
vivo can be seen from clinical and genetic evidence on functional relevance of these associations awaits futher
human patients with mutations in the gene for MeCP2; experimentation.
these individuals develop Rett syndrome—a progressive,
debilitating neurological disorder.
The second example regarding HDAC targeting in tran- V. CHROMATIN AND TRANSCRIPTION:
scriptional repression involves certain members of the nu- A SYNTHESIS
clear hormone receptor (NHR) superfamily. Some of these
proteins—GR, for example—are constitutively cytoplas- Scientists that devoted their careers to the study of chro-
mic and translocate to their site of action, the nucleus, only matin are understandably pleased with the progress of the