Recent advances in understanding the transcriptional output of higher eukaryotic genome have pointed to the importance of non-protein-coding genes as both regulatory and housekeeping factors. Our laboratory is interested in the role of this class of genes in cellular function, with special emphasis on the biogenesis and function of the long non-coding RNAs (lncRNAs), a ubiquitous and highly understudied subclass. Using the host response to viral infections and HIV in particular as a model system, we have shown that the antiviral response leads to a dramatic remodeling of the cellular transcriptional output, with a significant number of both protein-coding and non-protein-coding genes showing strong changes in gene expression. Work in our laboratory and elsewhere has pointed to a crucial regulatory role for a number of Interferon-induced lncRNAs, with some lncRNAs controlling the expression of multiple protein-coding genes. Ongoing research in our lab using a combination of computational and experimental approaches aims to further understand the role of interferon-induced lncRNAs during the acute phase of viral infection.
In addition to the lncRNAs differentially expressed due to the interferon response, several interferon-independent lncRNAs are strongly induced or repressed as a result of infection by viruses such as HIV. Another line of research in the lab is focused on understanding the larger regulatory network governing both the interferon-dependent and independent virally-induced changes in gene expression, especially those regulated by lncRNAs or impacting their biogenesis. Finally, after the acute phase of infection is over, transcriptional quiescence and reactivation of the cell and the integrated proviral genome are similarly accompanied by significant changes in the expression of lncRNAs which likely play additional regulatory roles in these processes. Understanding such long-term host-virus interactions and the role of lncRNAs in these processes are additional goals of research in our lab.
Research in our lab is focused on the role of long non-coding RNAs in higher eukaryotes. Large scale analyses of transcriptional output of the eukaryotic genomes have revealed the existence of a very large number of long non-coding transcripts. While the majority of them remain unstudied, current evidence suggest that the study of these mysterious transcripts is likely to provide answers to many remaining questions in biology of higher eukaryotes.
Using examples of mouse and human long non-coding RNAs as study models, we focus on in-depth analysis of their role in a number of fundamental biological processes:
Long non-coding RNAs in neurogenesis
We have shown that the expression of a long non-coding RNA is required for physiological neuronal differentiation. Interestingly, we could also show that forced ectopic expression of this RNA in myoblasts and fibroblasts leads to their reprogramming into neurons. Currently active projects in the lab address the mechanism of this intriguing observation and potential implications in regenerative medicine.
The role of long non-coding RNAs in neurodegenerative diseases
Another active project in the lab is based on our observation that a long non-coding RNA plays a major role in regulating the magnitude of the canonical stress response pathway. Considering the critical role of the stress response pathway in neurodegenerative diseases, we are in the process of defining the role of our RNA in neurodegenerative processes and its potential as a therapeutic measure.
Long non-coding RNAs and cancer
We have shown that the expression of a long non-coding RNA is progressively increased as breast and lung cancer cells acquire invasive and metastatic properties. We are in the process of defining the interactions of this RNA with the cellular pathways active in cancer, in addition to in vivo studies in the mouse to define the impact of altering the expression of this RNA on tumor progression.
Gooding A.J., Zhang B., Jahanbani F.K., Gilmore H.L., Chang J.C., Valadkhan S., Schiemann W.P. 2017. The lncRNA BORG Drives Breast Cancer Metastasis and Disease Recurrence. Sci Rep. 7:12698.
Garcia-Mesa Y., Jay T.R., Checkley M.A., Luttge B., Dobrowolski C., Valadkhan S., Landreth G.E., Karn J., Alvarez-Carbonell D. 2017. Immortalization of primary microglia: a new platform to study HIV regulation in the central nervous system. J Neurovirol. 2017 Feb;23(1):47-66.
Niazi, F. and Valadkhan, S. 2016. Analysis of Long Non-coding RNAs in RNA-seq data. Book chapter in Field Guidelines for Genetic Experimental Designs in High-Throughput Sequencing. Springer, in press.
Gunawardane, LS. and Valadkhan, S. 2016. lncRNA-mediated regulation of the interferon response. Review article, Virus Research 212:127-36.
Kambara H., Gunawardane L., Zebrowski E., Kostadinova L., Jobava R., Krokowski D., Hatzoglou M., Anthony D.D. and Valadkhan S. 2015. Regulation of interferon-stimulated gene BST2 by a lncRNA transcribed from a shared bidirectional promoter. Front. Immunol. 5:676.
Kambara, H., Niazi, F., Kostadinova L., Moonka D.K., Siegel C.T., Post A.B, Carnero E., Barriocanal M., Fortes P., Anthony D.D. and Valadkhan S. 2014. Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acid Research, 2014;42:10668-80.
Zhang, B., Gunawardane, L., Niazi, F., Jahanbani, F., Chen, X. and Valadkhan, S. 2014. A novel RNA motif mediates the strict nuclear localization of a long non-coding RNA. Mol. Cell. Biol., 34(12):2318-29.
Niazi F., Valadkhan S. 2012. Computational analysis of functional long non-coding RNAs reveals lack of peptide-coding capacity and parallels with 3'UTRs. RNA 18:825-43.