Prostate cancer afflicts 1 in 4 men by the age of 75 and remains a major public health concern in the United States. Despite some success in disease diagnosis and treatment the molecular parameters that influence the transition from prostatic intraepithelial neoplasia to prostate cancer has remained elusive. The long-term goal of our research is to determine the fundamental molecular mechanisms of epigenetic gene transcription in human biology and disease, particularly human prostate cancer. We focus on the role of Polycomb repressive complexes (PRCs) in transcriptional control of the INK4a/ARF locus, gene products of which are the primary mediators of oncogene-induced senescence. PRC-directed gene silencing is mediated by methylation of histone H3 lysine 27 (H3K27me) at target loci in chromatin that is initiated by the lysine methyltransferase EZH2 of the PRC2 and followed by H3K27me association with the PRC1 by binding to chromobox (CBX) proteins, resulting in chromatin condensation and target gene silencing. Our recent study reveals that the silencing activity of PRC1 for the INK4a/ARF locus requires CBX7 interactions with a non-coding RNA transcript ANRIL (the antisense RNA of INK4a locus) and H3K27me via its conserved chromodomain, highlighting a direct role of long non-coding RNA in epigenetic transcriptional silencing. CBX7 and other key components of PRCs that play a key role in cellular lifespan extension by repressing the INK4a/ARF locus are over-expressed in prostate cancer. We further observed in our study markedly elevated expression of ANRIL, CBX7 and EZH2 and a corresponding decrease in p16[Ink4a] expression in prostate cancer as compared to normal prostate epithelial cells. However, the molecular mechanism of non-coding RNA in PRC-directed gene silencing is not clear. In this project, we aim to determine the molecular underpinning of the functional interplay between non-coding RNA and H3K27me in gene silencing by the PRCs in normal prostate epithelial cells, as well as during the conversion of prostatic intraepithelial neoplasia into prostate carcinoma using combined chromatin/cell biology and structural/chemical biology methods. We expect that the results emerging from our studies including novel chemical tools will have profound impact on a better understanding of prostate cancer biology and future advance of therapeutic means for prognosis and prevention of human prostate cancer.
Non-coding RNA transcripts play a fundamental role in epigenetic control of gene expression in the human genome, but the underlying molecular mechanism has remained elusive. In this project we will investigate how non-coding RNAs function as the molecular circuitry to regulate the epigenetic character of the human genome. The outcome of our study is expected to provide a new understanding of the role of ncRNAs to guide the Polycomb group proteins that govern the epigenome state of human biology of health and disease, particularly prostate cancer.
|Nudelman, German; Frasca, Antonio; Kent, Brandon et al. (2018) High resolution annotation of zebrafish transcriptome using long-read sequencing. Genome Res 28:1415-1425|
|Aguilo, Francesca; Walsh, Martin J (2017) The N6-Methyladenosine RNA modification in pluripotency and reprogramming. Curr Opin Genet Dev 46:77-82|
|Li, Jun; Rodriguez, Yoel; Cheng, Chunming et al. (2017) EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer. Mol Cell Biol 37:|
|Zhang, Qiang; Zeng, Lei; Zhao, Chengcheng et al. (2016) Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure 24:1606-12|
|Di Cecilia, Serena; Zhang, Fan; Sancho, Ana et al. (2016) RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells. Cancer Res 76:5615-5627|
|Aguilo, Francesca; Li, SiDe; Balasubramaniyan, Natarajan et al. (2016) Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1?. Cell Rep 14:479-492|
|Aguilo, Francesca; Di Cecilia, Serena; Walsh, Martin J (2016) Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease. Curr Top Microbiol Immunol 394:29-39|
|Kent, Brandon; Magnani, Elena; Walsh, Martin J et al. (2016) UHRF1 regulation of Dnmt1 is required for pre-gastrula zebrafish development. Dev Biol 412:99-113|
|Zhang, Fan; Ren, Chunyan; Lau, Kwun Kit et al. (2016) A network medicine approach to build a comprehensive atlas for the prognosis of human cancer. Brief Bioinform 17:1044-1059|
|Lee, Dung-Fang; Walsh, Martin J; Aguiló, Francesca (2016) ZNF217/ZFP217 Meets Chromatin and RNA. Trends Biochem Sci 41:986-988|
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