Metastasis is a main cause of cancer death, and a hurdle in cancer therapy. Since altered gene expression significantly contributes to metastasis, understanding the mechanism of metastasis-related gene expression is necessary for developing new therapeutic modalities. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) highly expressed in many cancers. Upregulation of MALAT1 has been linked to poor prognosis, increased tumor metastasis and cell cycle/metastasis-related gene expression. Despite its close association with cancer, exact cellular functions of MALAT1 remain elusive. Recent efforts on human and mouse knockout systems to study the loss-of-function phenotypes of MALAT1 failed to demonstrate noticeable changes in global gene expression, raising a possibility that there may be unidentified molecular mechanisms of MALAT1 locus-mediated gene expression control. We have studied a novel nuclear speckle protein, SON, and our recent effort on chromatin immunoprecipitation with SON antibody and sequencing (ChIP-seq) revealed that SON strongly interacts with the immediate downstream DNA sequence of the MALAT1 gene 3' end, while it interacts with the promoter or the first exon of many other genes associated with cell cycle/metastasis. Moreover, the DNA sequence near the 3' end of the MALAT1 gene possesses many characteristic features of a distal regulatory element, according to ENCODE (Encyclopedia of DNA Elements) data. We hypothesize that the open/active MALAT1 locus in metastatic cancer cells has enhanced chromatin interaction through the DNA sequence located immediately downstream from the MALAT1 gene, and SON is a critical component mediating chromatin interaction between this genomic locus and promoter/enhancer sequences of other genes, resulting in co- regulation of multiple metastasis/cancer-related genes. To test this hypothesis, we propose following specific aims; (1) Identify genome-wide chromatin interactions of the MALAT1 locus in normal lung epithelial cells and metastatic lung cancer cells, (2) Investigate the role of SON in chromatin interaction of the MALAT1 locus and expression of cell cycle/metastasis genes in metastatic lung cancer cells. We will use an enhanced method of chromosome conformation capture and deep sequencing (e4C) to establish the MALAT1 chromatin interaction profile, and to identify the role of SON in chromatin interaction and gene expression related to cell cycle/metastasis. Elucidating the role of MALAT1 locus chromatin interaction in controlling global gene expression will provide novel insights into the action of this locus in cancer. Furthermore, investigating the role of SON in MALAT1-mediated gene regulation will serve as a basis of targeting SON together with the genomic locus of MALAT1 for treatment and prevention of metastatic cancer.
Cancer metastasis is often caused by altered gene expression, and the long-range chromatin interaction is an emerging mechanism of global gene regulation. The goal of this project is to define distal regulatory functions of the DNA sequence located at the genomic locus of the long non-coding RNA MALAT1 which is highly expressed in metastatic cancer, and the role of SON in mediating long-range chromatin interactions and metastasis gene regulation at this location. New insights into cooperative functions of the genomic locus of MALAT1 and its protein partner SON in genome-wide chromatin interaction and gene regulation will lead to identification of novel therapeutic targets for metastatic cancer.
| Kim, Jung-Hyun; Baddoo, Melody C; Park, Eun Young et al. (2016) SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes. Mol Cell 61:859-73 |
| Kim, Jung-Hyun; Shinde, Deepali N; Reijnders, Margot R F et al. (2016) De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet 99:711-719 |
