Dataset Information

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

ABSTRACT: Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.

SUBMITTER: He H

PROVIDER: S-EPMC3653903 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

He Huiling H Li Wei W Wu Dayong D Nagy Rebecca R Liyanarachchi Sandya S Akagi Keiko K Jendrzejewski Jaroslaw J Jiao Hong H Hoag Kevin K Wen Bernard B Srinivas Mukund M Waidyaratne Gavisha G Wang Rui R Wojcicka Anna A Lattimer Ilene R IR Stachlewska Elzbieta E Czetwertynska Malgorzata M Dlugosinska Joanna J Gierlikowski Wojciech W Ploski Rafal R Krawczyk Marek M Jazdzewski Krystian K Kere Juha J Symer David E DE Jin Victor V Wang Qianben Q de la Chapelle Albert A

PloS one 20130514 5

Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 3 ...[more]

PMID: 23690926

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Project description:In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. Here, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, we explore the transcriptional interactomes of three mouse cells of progressive lineage commitment, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Our global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. Our study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.

Dataset Information

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

Publications

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

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