We have recently identified a class of long ncRNA termed ncRNA-activating (ncRNA-a), which can activate the expression of neighboring protein-coding genes at long distances. Our current data suggest that ncRNA-a function by associating with the co-activator complex, Mediator, to promote DNA looping. The association between ncRNA-a and the Mediator complex will be investigated to understand how specificity for target selection is achieved and to pinpoint the contribution of RNA to transcriptional activation. The three Aims are designed to provide a thorough molecular understanding of the activating ncRNAs and their association with the Mediator complex.
Aim1 describes experiments that examine the molecular basis for ncRNA-a nuclear localization and transcriptional activation.
Aim 2 describes experiments to delineate the molecular basis of ncRNA-a and the Mediator complex interaction. We will determine whether ncRNA-a is critical for the recruitment of Mediator to its target sites and perform structure/function experiments to assess the importance of ncRNA-a/Mediator interaction in transcriptional activation.
Aim3 will assess the molecular basis by which ncRNA-a activates the CDK8 kinase activity. Importantly, recurrent mutations in Med12 subunit of Mediator complex, which is critical for kinase activity, result in development of multiple human cognitive syndromes and a benign smooth muscle neoplasm. Therefore, we will test the hypothesis that such mutations affect the kinase activity of Mediator by disrupting its association with the ncRNA-a.
Public Health Relevance This proposal is aimed at characterizing the vast amount of the human genome that encodes non-protein coding RNAs (ncRNAs). Our results suggest that a number of these ncRNAs act similarly to previously defined enhancers to activate transcription of important developmental regulators. Since enhancers have been shown to be mis- regulated in cancer, our work will have a broad impact in the field of developmental biology and oncogenesis.
|Cheng, G; Liu, F; Asai, T et al. (2016) Loss of p300 accelerates MDS-associated leukemogenesis. Leukemia :|
|Yang, Mei; Liang, Chen; Swaminathan, Kunchithapadam et al. (2016) A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv 2:e1601167|
|Li, Na; Li, Yuanyuan; Lv, Jie et al. (2016) ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell 63:470-84|
|Kim, Tae-Kyung; Shiekhattar, Ramin (2016) Diverse regulatory interactions of long noncoding RNAs. Curr Opin Genet Dev 36:73-82|
|Witt, A E; Lee, C-W; Lee, T I et al. (2016) Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene :|
|Chen, Fei Xavier; Woodfin, Ashley R; Gardini, Alessandro et al. (2015) PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II. Cell 162:1003-15|
|Lai, Fan; Gardini, Alessandro; Zhang, Anda et al. (2015) Integrator mediates the biogenesis of enhancer RNAs. Nature 525:399-403|
|Kim, Tae-Kyung; Shiekhattar, Ramin (2015) Architectural and Functional Commonalities between Enhancers and Promoters. Cell 162:948-59|
|Gardini, Alessandro; Shiekhattar, Ramin (2015) The many faces of long noncoding RNAs. FEBS J 282:1647-57|
|Bonasio, Roberto; Shiekhattar, Ramin (2014) Regulation of transcription by long noncoding RNAs. Annu Rev Genet 48:433-55|
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