Aberrant DNA Methylation of OLIG1, a Novel Prognostic Factor in Non-Small Cell Lung Cancer

Brena, Romulo M.; Morrison, Carl; Liyanarachchi, Sandya; Jarjoura, David; Davuluri, Ramana V.; Otterson, Gregory A.; Reisman, David; Glaros, Selina; Rush, Laura J.; Plass, Christoph

doi:10.1371/journal.pmed.0040108

Cited by 52 publications

(31 citation statements)

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“…Pathological deregulation of such scaffolds is likely to have deleterious effects. Of note, BAHD1 expression is down-regulated in invasive lung cancer cells (8), and a recent study indicated reduced levels of BAHD1 transcript in RNA in blood samples from patients with double tumors compared with patients with single tumors (http:// www.nextbio.com/b/home/home.nb?q ϭ BAHD1). Our findings support the hypothesis that BAHD1 acts as a tumor suppressor through the silencing of cancer-related genes, such as IGF2, in adult tissues.…”

Section: Discussionmentioning

confidence: 99%

“…During a screen for human proteins that interact with microbial factors and that might play a role in bacterial pathogenicity, we identified a putative chromatin-associated protein, bromo adjacent homology domaincontaining protein 1 (BAHD1), which remains uncharacterized. One study correlated repression of the BAHD1 gene to poor prognosis in lung cancer (8), raising the possibility that BAHD1 might act as a tumor suppressor. This connection between BAHD1 and pathological processes prompted us to characterize the function of this protein.…”

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confidence: 99%

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Human BAHD1 promotes heterochromatic gene silencing

Bierne

Tham

Batsché

et al. 2009

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

125

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Gene silencing via heterochromatin formation plays a major role in cell differentiation and maintenance of homeostasis. Here we report the identification and characterization of a novel heterochromatinization factor in vertebrates, bromo adjacent homology domaincontaining protein 1 (BAHD1). This nuclear protein interacts with HP1, MBD1, HDAC5, and several transcription factors. Through electron and immunofluorescence microscopy studies, we show that BAHD1 overexpression directs HP1 to specific nuclear sites and promotes the formation of large heterochromatic domains, which lack acetyl histone H4 and are enriched in H3 trimethylated at lysine 27 (H3K27me3). Furthermore, ectopically expressed BAHD1 colocalizes with the heterochromatic inactive X chromosome (Xi). The BAH domain is required for BAHD1 colocalization with H3K27me3, but not with the Xi chromosome. As highlighted by whole genome microarray analysis of BAHD1 knockdown cells, BAHD1 represses several proliferation and survival genes, in particular the insulin-like growth factor II gene (IGF2). When overexpressed, BAHD1 specifically binds the CpG-rich P3 promoter of IGF2, which increases MBD1 and HDAC5 targeting at this locus. This region contains DNA-binding sequences for the transcription factor SP1, with which BAHD1 coimmunoprecipitates. Collectively, these findings provide evidence that BAHD1 acts as a silencer by recruiting at specific promoters a set of proteins that coordinate heterochromatin assembly.BAH domain ͉ epigenetics ͉ heterochromatin ͉ HP1 ͉ polycomb G ene repression in eukaryotes in response to developmental or environmental signals is a complex multistep process requiring the concerted action of many cellular factors, including DNA-binding transcription factors and cofactors. It also involves chromatin components and chromatin-binding/-modifying proteins, which are implicated in the establishment and maintenance of a condensed chromatin state, also referred to as facultative heterochromatin (1). Deregulation of these chromatin regulatory factors and aberrant chromatin modifications play important roles in various human diseases, including cancers, developmental abnormalities, and neurologic disorders (2-6). Moreover, several recent reports have linked histone modifications and infectious diseases (7). During a screen for human proteins that interact with microbial factors and that might play a role in bacterial pathogenicity, we identified a putative chromatin-associated protein, bromo adjacent homology domaincontaining protein 1 (BAHD1), which remains uncharacterized. One study correlated repression of the BAHD1 gene to poor prognosis in lung cancer (8), raising the possibility that BAHD1 might act as a tumor suppressor. This connection between BAHD1 and pathological processes prompted us to characterize the function of this protein.BAHD1 is so named because it contains a C-terminal BAH domain, which is found in several chromatin-binding proteins involved in transcriptional repression (9), including the yeast Sir3 protein (10). We invest...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human BAHD1 promotes heterochromatic gene silencing

Bierne

Tham

Batsché

et al. 2009

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

125

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“…Nonquantitative MSP may be useful for these applications, especially when quantitative levels would have little value due to variable sample composition, such as may occur with very small biopsies or cytologic specimens. Finally, genome-wide comparative analysis of CpG methylation patterns in normal tissues and tumors may require microarray approaches, 53 although validation requirements for such techniques are inherently complex and not yet well-established.…”

Section: Selection Of Methods For Testing Methylation Of Specific Cpgmentioning

confidence: 99%

CpG Methylation Analysis—Current Status of Clinical Assays and Potential Applications in Molecular Diagnostics

Sepulveda

Jones

Ogino

et al. 2009

The Journal of Molecular Diagnostics

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“…13 Overexpression of DNA methyltranferases DNMT1, DNMT3A and DNMT3B has been described in NSCLC especially among smoker patients, and correlates with hypermethylation of tumor suppressor gene such as p16 INK4a , FHIT and RARβ. 17,18 Furthermore, polymorphisms that influence expression of the DNMT3B gene have been connected with risk of lung cancer.…”

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confidence: 99%

“…Consistently, genome wide analyses have pointed to the fact that the extend of promoter DNA hypermethylation is probably under-appreciated. [13][14][15][16] By using a high-throughput global expression profiling approach, Shames et al recently identified 132 genes that are methylated with high penetrance in lung cancer cells. 16 More strikingly, the analysis performed by Brena et al supports the notion that 4.8% of all CpG island promoters might be aberrantly methylated, suggesting that the expression of about 1,400 genes might be disturbed These modifications can either favor (e.g., acetylation, methylation) or inhibit (e.g., methylation) the access to the chromatin and are involved in all DNA-based processes described so far.…”

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confidence: 99%