Research Summary

Studying lineage specificity and role of BDNF ncRNA expression during neural stem cell differentiation

Analyses of eukaryotic transcriptome have revealed the presence of numerous RNA polymerase II (Pol II) transcripts of unknown function in intergenic regions. These findings challenged the previous dogma that transcription is limited to well-defined functional units known as canonical genes. Interestingly, studies of individual ncRNAs have assigned important regulatory roles to them. Non-coding (nc) transcripts frequently overlap with protein-coding genes, and in this scenario nc transcription may result in transcriptional interference of down-stream-positioned genes and thus result in repression. Recent studies revealed that it could also act at the levels of nucleosome remodeling and change in chromatin modification profile; however, the exact mechanisms involved are not well understood. NcRNAs have been shown to be involved in most biological phenomena, including development and physiology of the nervous system. Based on the role of BDNF in memory and neuron regeneration, BDNF is currently one of the targets for anti-depression studies, candidate fear and memory related disorders. Improper BDNF expression or function has been linked to a number of neuropsychiatric and neurodegenerative diseases such as Rett syndrome, Alzheimer, Schizophrenia, Huntington disease etc.

The proposed project aims at extending our knowledge on the genetic factors and the functional processes of ncRNA mediated regulation of BDNF mRNA, with emphasis on the relationship between BDNF and emotional stress. In vivo and in vitro approaches will be used to study the role of BDNF isoforms in neural stem cell differentiation combined with molecular biology techniques and expertise from Vaidya lab (TIFR, India) and Castren lab (Neuroscience Centre, Finland). Understanding BDNF transcriptional regulation and developmental expression may help design potent therapeutic strategies utilizing siRNAs against specific BDNF regions regulating ncRNA and mRNA expression .

Figure Legend: Model describing ncRNA mediated regulation of a protein-coding gene (pho1) in S. pombe.In the absence of phosphate in the media pho1 mRNA expression is induced resulting in high acid phosphatase activity. However, in high phosphate conditions, long ncRNA (lncRNA) is transcribed from upstream of pho1 mRNA promoter. Transcription of lncRNA results in transcriptional downregulation of pho1 mRNA and protein levels. Transcription termination and post-transcriptional degradation of ncRNA is dependent on the exosome complex. Thus, via transcription of lncRNA, pho1 mRNA expression is regulated in response to extracellular phosphate in the environment.