13q14 Deletion May Involve Epigenetic Defect

[Guest guest]

[Epigenetics is an inheritable change that doesn't involve the base

pairs of the DNA molecule. It involves gene expression and

interaction. One example of this involves methylation of the DNA.]

1: Proc Natl Acad Sci U S A. 2006 May 9; [Epub ahead of print]

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Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an

epigenetic tumor-suppressor mechanism.

Mertens D, Wolf S, Tschuch C, Mund C, Kienle D, Ohl S, Schroeter P,

Lyko F, Dohner H, Stilgenbauer S, Lichter P.

Department of Molecular Genetics and Epigenetics, Deutsches

Krebsforschungszentrum, INF 280, 69120 Heidelberg, Germany.

Genomic material from chromosome band 13q14.3 distal to the

retinoblastoma locus is recurrently lost in a variety of human

neoplasms, indicating an as-yet-unidentified tumor-suppressor

mechanism. No pathogenic mutations have been found in the minimally

deleted region until now. However, in B cell chronic lymphocytic

leukemia tumors with loss of one copy of the critical region,

respective candidate tumor-suppressor genes are down-regulated by a

factor >2, which would be expected by a normal gene-dosage effect.

This finding points to an epigenetic pathomechanism.

We find that the two copies of the critical region replicate

asynchronously, suggesting differential chromatin packaging of the

two copies of 13q14.3. Although we also detect monoallelic silencing

of genes localized in the critical region, monoallelic expression

originates from either the maternal or paternal copy, excluding an

imprinting mechanism.

DNA methylation analyses revealed one CpG island of the region to be

methylated. DNA demethylation of this CpG island and global histone

hyperacetylation induced biallelic expression, whereas replication

timing was not affected. We propose that differential replication

timing represents an early epigenetic mark that distinguishes the two

copies of 13q14.3, resulting in differential chromatin packaging and

monoallelic expression.

Accordingly, deletion of the single active copy of 13q14.3 results in

significant down-regulation of the candidate genes and loss of

function, providing a model for the interaction of genetic lesions

and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic

leukemia.

PMID: 16684883 [PubMed - as supplied by publisher]