Epigenetic Inactivation of the <i>HOXA</i> Gene Cluster in Breast Cancer

Novák, Petr; Jensen, Taylor J.; Oshiro, Marc M.; Wozniak, Ryan J.; Nouzová, Marcela; Watts, George S.; Klimecki, Walter T.; Kim, Christina; Futscher, Bernard W.

doi:10.1158/0008-5472.can-06-2761

Cited by 109 publications

(119 citation statements)

References 20 publications

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“…coexpressed genes ͉ nuclear lamina P revious studies by others and us have shown that many coexpressed tissue-specific genes are organized in large continuous clusters on chromosomes of diverse species (1)(2)(3), and similar clustering has been observed for the genes deregulated in diverse diseases (4)(5)(6)(7)(8). These findings imply that higherorder chromatin structure may be involved in regulation of extensive multigenic regions in both normal development and its pathological disruptions.…”

mentioning

confidence: 62%

The B-type lamin is required for somatic repression of testis-specific gene clusters

Shevelyov

Lavrov

Mikhaylova

et al. 2009

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

123

118

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Large clusters of coexpressed tissue-specific genes are abundant on chromosomes of diverse species. The genes coordinately misexpressed in diverse diseases are also found in similar clusters, suggesting that evolutionarily conserved mechanisms regulate expression of large multigenic regions both in normal development and in its pathological disruptions. Studies on individual loci suggest that silent clusters of coregulated genes are embedded in repressed chromatin domains, often localized to the nuclear periphery. To test this model at the genome-wide scale, we studied transcriptional regulation of large testis-specific gene clusters in somatic tissues of Drosophila. These gene clusters showed a drastic paucity of known expressed transgene insertions, indicating that they indeed are embedded in repressed chromatin. Bioinformatics analysis suggested the major role for the B-type lamin, LamDmo, in repression of large testis-specific gene clusters, showing that in somatic cells as many as three-quarters of these clusters interact with LamDmo. Ablation of LamDmo by using mutants and RNAi led to detachment of testis-specific clusters from nuclear envelope and to their selective transcriptional up-regulation in somatic cells, thus providing the first direct evidence for involvement of the B-type lamin in tissue-specific gene repression. Finally, we found that transcriptional activation of the lamina-bound testis-specific gene cluster in male germ line is coupled with its translocation away from the nuclear envelope. Our studies, which directly link nuclear architecture with coordinated regulation of tissue-specific genes, advance understanding of the mechanisms underlying both normal cell differentiation and developmental disorders caused by lesions in the B-type lamins and interacting proteins.coexpressed genes ͉ nuclear lamina P revious studies by others and us have shown that many coexpressed tissue-specific genes are organized in large continuous clusters on chromosomes of diverse species (1-3), and similar clustering has been observed for the genes deregulated in diverse diseases (4-8). These findings imply that higherorder chromatin structure may be involved in regulation of extensive multigenic regions in both normal development and its pathological disruptions. In support of this suggestion, alterations in chromatin structure across large multigenic domains have been correlated to changes in gene expression (9-13). Repressed multigenic regions are frequently localized to nuclear periphery (14), and a number of studies linked derepression/ activation of genetic loci with their translocation away from the nuclear envelope (15-21). These observations suggest that tethering of genetic loci to nuclear lamina causes their silencing. Recent reports of repression of integrated transgenes and adjacent endogenous genes upon their artificial recruitment to the nuclear envelope (21, 22) support this hypothesis; however, similar studies on different loci did not show repression (23,24) indicating that silencing at nuclear ...

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mentioning

confidence: 62%

The B-type lamin is required for somatic repression of testis-specific gene clusters

Shevelyov

Lavrov

Mikhaylova

et al. 2009

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

123

118

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“…The HOXA5 promoter region was methylated in 16 of 20 p53-negative breast tumor specimens (29). While this manuscript was in preparation, methylation of the HOXA gene cluster in breast cancer was reported (30)…”

Section: Discussionmentioning

confidence: 93%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

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

260

221

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De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancerassociated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7-and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.DNA methylation ͉ HOX genes ͉ chromatin ͉ Polycomb

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“…In phase I of our two-phase strategy to characterize epigenetic phenomena in DLBCL, we measured DNA methylation levels in seven ABC-DLBCL and seven GCB-DLBCL tumors using CpG island microarray assays 12,16,17 (Figure 1). This provided a rapid means of evaluating the methylation-dependent cleavage of 442 unique gene-associated CpG islands by McrBC endonuclease (Supplementary Table 1 and Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status

et al. 2008

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In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEU-ROD1, ONECUT2 and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of 67 genes proximal (within 500 bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted.

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Epigenetic Inactivation of the HOXA Gene Cluster in Breast Cancer

Cited by 109 publications

References 20 publications

The B-type lamin is required for somatic repression of testis-specific gene clusters

The B-type lamin is required for somatic repression of testis-specific gene clusters

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status

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