Monoallelic gene expression: a repertoire of recurrent themes

Goldmit, Maya; Bergman, Yehudit

doi:10.1111/j.0105-2896.2004.00158.x

Cited by 77 publications

(68 citation statements)

References 172 publications

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“…In imprinting, discrimination of the two gene copies is achieved through epigenetic chromatin modifications, such as differential DNA methylation (13), histone modifications (14), and replication timing (15). We visualized asynchronous replication timing by fluorescence in situ hybridization under experimental conditions that separate replicated chromatids (16,17).…”

Section: Resultsmentioning

confidence: 99%

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

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

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

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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 downregulated 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 downregulation 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.DNA methylation ͉ monoallelic expression ͉ replication timing

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Section: Resultsmentioning

confidence: 99%

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

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

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

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“…We could not confirm that RPS6KA2 is imprinted using DNA/RNA derived from lymphoblastoid cell lines from three independent CEPH families. Therefore, the most probable explanation for monoallelic expression of RPS6KA2 is that it is a randomly occurring event, although we sampled several normal ovaries and in each case it was expressed monoallelically (Sano et al, 2001;Lo et al, 2003;Goldmit and Bergman, 2004). Further, when the HOSE cell line is treated with 5-azacytidine, the levels of RPS6KA2 expression are increased two-fold, suggesting silencing by methylation in one allele.…”

Section: Discussionmentioning

confidence: 98%

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

et al. 2006

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We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.

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“…In this context, the JCκ region gets monoallelically demethylated and this demethylated allele undergoes rearrangement first (Mostoslavsky et al, 1998). The second allele stays in a repressive environment and somehow can get demethylated, if the rearrangement on the first Igκ allele is nonproductive (Goldmit and Bergman, 2004). More extensive studies on DNA methylation of the IgH locus could potentially help to elucidate aspects of accessibility control within this locus.…”

Section: Chromatin Modificationsmentioning

confidence: 99%

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Perlot

Alt

2008

Advances in Immunology

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Immunoglobulin variable region exons are assembled from discontinuous variable (V), diversity (D), and joining (J) segments by the process of V(D)J recombination. V(D)J rearrangements of the immunoglobulin heavy chain (IgH) locus are tightly controlled in a tissue-specific, ordered and allele-specific manner by regulating accessibility of V, D, and J segments to the recombination activating gene proteins which are the specific components of the V(D)J recombinase. In this review we discuss recent advances and established models brought forward to explain the mechanisms underlying accessibility control of V(D)J recombination, including research on germline transcripts, spatial organization, and chromatin modifications of the immunoglobulin heavy chain (IgH) locus. Furthermore, we review the functions of well-described and potential new cis-regulatory elements with regard to processes such as V(D)J recombination, allelic exclusion, and IgH class switch recombination.

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Monoallelic gene expression: a repertoire of recurrent themes

Cited by 77 publications

References 172 publications

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

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

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

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