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Computational and experimental identification of novel human imprinted genes.

ABSTRACT: Imprinted genes are essential in embryonic development, and imprinting dysregulation contributes to human disease. We report two new human imprinted genes: KCNK9 is predominantly expressed in the brain, is a known oncogene, and may be involved in bipolar disorder and epilepsy, while DLGAP2 is a candidate bladder cancer tumor suppressor. Both genes lie on chromosome 8, not previously suspected to contain imprinted genes. We identified these genes, along with 154 others, based on the predictions of multiple classification algorithms using DNA sequence characteristics as features. Our findings demonstrate that DNA sequence characteristics, including recombination hot spots, are sufficient to accurately predict the imprinting status of individual genes in the human genome.

SUBMITTER: Luedi PP

PROVIDER: S-EPMC2099581 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Computational and experimental identification of novel human imprinted genes.

Luedi Philippe P PP Dietrich Fred S FS Weidman Jennifer R JR Bosko Jason M JM Jirtle Randy L RL Hartemink Alexander J AJ

Genome research 20071130 12

Imprinted genes are essential in embryonic development, and imprinting dysregulation contributes to human disease. We report two new human imprinted genes: KCNK9 is predominantly expressed in the brain, is a known oncogene, and may be involved in bipolar disorder and epilepsy, while DLGAP2 is a candidate bladder cancer tumor suppressor. Both genes lie on chromosome 8, not previously suspected to contain imprinted genes. We identified these genes, along with 154 others, based on the predictions o ...[more]

PMID: 18055845

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Project description:Metazoan core promoters, which direct the initiation of transcription by RNA polymerase II (Pol II), may contain short sequence motifs termed core promoter elements/motifs (e.g. the TATA box, initiator (Inr) and downstream core promoter element (DPE)), which recruit Pol II via the general transcription machinery. The DPE was discovered and extensively characterized in Drosophila, where it is strictly dependent on both the presence of an Inr and the precise spacing from it. Since the Drosophila DPE is recognized by the human transcription machinery, it is most likely that some human promoters contain a downstream element that is similar, though not necessarily identical, to the Drosophila DPE. However, only a couple of human promoters were shown to contain a functional DPE, and attempts to computationally detect human DPE-containing promoters have mostly been unsuccessful. Using a newly-designed motif discovery strategy based on Expectation-Maximization probabilistic partitioning algorithms, we discovered preferred downstream positions (PDP) in human promoters that resemble the Drosophila DPE. Available chromatin accessibility footprints revealed that Drosophila and human Inr+DPE promoter classes are not only highly structured, but also similar to each other, particularly in the proximal downstream region. Clustering of the corresponding sequence motifs using a neighbor-joining algorithm strongly suggests that canonical Inr+DPE promoters could be common to metazoan species. Using reporter assays we demonstrate the contribution of the identified downstream positions to the function of multiple human promoters. Furthermore, we show that alteration of the spacing between the Inr and PDP by two nucleotides results in reduced promoter activity, suggesting a spacing dependency of the newly discovered human PDP on the Inr. Taken together, our strategy identified novel functional downstream positions within human core promoters, supporting the existence of DPE-like motifs in human promoters.

Dataset Information

Computational and experimental identification of novel human imprinted genes.

Publications

Computational and experimental identification of novel human imprinted genes.

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