Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Rice, Judd C.

doi:10.1093/nar/28.17.3233

Cited by 86 publications

(54 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our chromatin immunoprecipitation assays showed that both histone H3 and H4 are deacetylated in cell lines where CHFR is silent, and that 5-aza-dC and TSA act synergistically to enhance CHFR expression. Histone deacetylation thus appears to be involved in the methylation-dependent silencing of CHFR, just as in the silencing of p16INK4A, p14ARF, and BRCA1 (13,23). Nevertheless, our analysis showed that reducing DNA methylation can restore expression of CHFR despite histone deacetylation, indicating DNA methylation to be a more potent determinant of CHFR expression than histone acetylation.…”

Section: Discussionmentioning

confidence: 63%

Epigenetic inactivation of CHFR in human tumors

Toyota

Sasaki

Satoh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

186

168

View full text Add to dashboard Cite

Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.DNA methylation ͉ DNA methyltransferase ͉ mitotic checkpoint ͉ histone deacetylation

show abstract

Section: Discussionmentioning

confidence: 63%

Epigenetic inactivation of CHFR in human tumors

Toyota

Sasaki

Satoh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

186

168

View full text Add to dashboard Cite

show abstract

“…These data indicate that promoter hypermethylation may be secondary to the transcriptional repression and may lead to a stable inactive chromatin state, similar to the inactive X chromosome, the imprinted gene locus, and BRCA1 gene inactivation (Jeppesen and Turner, 1993;Rice and Futscher, 2000;Saitoh and Wada, 2000). Further study is necessary to clarify the precise mechanisms whereby DNA hypermethylation and histone deacetylation are involved in the alteration of chromatin structure and promoter inactivation.…”

Section: Nakayama Et Almentioning

confidence: 96%

The Role of Epigenetic Modifications in Retinoic Acid Receptor β2 Gene Expression in Human Prostate Cancers

Nakayama

Watanabe

Yamanaka

et al. 2001

Laboratory Investigation

107

View full text Add to dashboard Cite

SUMMARY:The retinoic acid receptor (RAR) ␤ gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RAR␤, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RAR␤ mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RAR␤2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RAR␤2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2'-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RAR␤2 in RAR␤2-negative cells. These data suggest that the RAR␤2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa. (Lab Invest 2001, 81:1049 -1057.

show abstract

“…This interesting difference between promoter-terminator region associations in the different breast tumor cell lines may relate to their different properties. Significantly, BRCA1 has been shown to have altered promoter DNA-protein interactions in a cell line in which BRCA1 expression is undetectable (30). Although BRCA1 repression may be caused by the associated promoter hypermethylation, an alternate explanation could be the formation of an aberrant chromatin loop between the 5Ј and 3Ј ends of the gene.…”

Section: (B) (I) Mapmentioning

confidence: 99%

Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene

Tan-Wong

French

Proudfoot

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

134

121

View full text Add to dashboard Cite

The 85-kb breast cancer-associated gene BRCA1 is an established tumor suppressor gene, but its regulation is poorly understood. We demonstrate by gene conformation analysis in both human cell lines and mouse mammary tissue that gene loops are imposed on BRCA1 between the promoter, introns, and terminator region. Significantly, association between the BRCA1 promoter and terminator regions change upon estrogen stimulation and during lactational development. Loop formation is transcription-dependent, suggesting that transcriptional elongation plays an active role in BRCA1 loop formation. We show that the BRCA1 terminator region can suppress estrogen-induced transcription and so may regulate BRCA1 expression. Significantly, BRCA1 promoter and terminator interactions vary in different breast cancer cell lines, indicating that defects in BRCA1 chromatin structure may contribute to dysregulated expression of BRCA1 seen in breast tumors.transcriptional regulation ͉ chromatin conformation ͉ gene repression ͉ mammary gland ͉ breast cancer E xpression of the tumor suppressor gene BRCA1 is reduced in a significant proportion of human breast tumors (1-3). Although up to one-third of these cases can be explained by promoter hypermethylation (4, 5) for most cases the cause is unknown. Understanding the underlying mechanisms of BRCA1 gene repression is critical for generating effective strategies for re-establishing BRCA1 expression and thus restoring its tumor suppressor function.Transcriptional initiation of protein-coding genes depends on a coordinated interplay of protein-DNA and protein-protein interactions (6). In addition to the assembly of RNA polymerase II (Pol II) with basal transcription machinery on the gene promoter, numerous transcription factors are recruited to either activate or repress transcription. As many of these factors associate with DNA sequences distant to the promoter, transcriptional regulation often involves long-range DNA associations, possibly mediated by the formation of chromatin loops (7). Chromatin loops can be detected by the chromosome conformation capture (3C) technique (8), which involves formaldehyde cross-linking of chromatin in live cells, digesting DNA with restriction enzymes, and then religating DNA in dilute solution to favor intramolecular ligation. PCR is then used to detect the presence of such ligation products. 3C has been used to study the normal regulation of genes in multiple eukaryotic species and supports a looping model for gene activation and repression. For example, transcriptional activation of the ␤-globin gene in mouse is associated with interactions between multiple hypersensitive sites spanning Ͼ50 kb of DNA (9), whereas repression of the maternal IGF2 gene is linked to a long-range association between IGF2 and H19 loci, restricting access to an IGF2 enhancer (10).Several human diseases are associated with mutations in long-range control elements (11). Examples include Campomelic dysplasia, which can be caused by deletion of critical regulatory elements Ϸ50 kb upst...

show abstract

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Cited by 86 publications

References 33 publications

Epigenetic inactivation of CHFR in human tumors

Epigenetic inactivation of CHFR in human tumors

The Role of Epigenetic Modifications in Retinoic Acid Receptor β2 Gene Expression in Human Prostate Cancers

Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene

Contact Info

Product

Resources

About