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CURRENT RESEARCH

Broad Area of Research: RNA biology (microRNA, piRNA, ceRNA, lncRNA), Stem cells, Functional genomics, Epigenomics and Cancer

Our lab focuses on study of crosstalks or interference mediated by regulatory non-coding RNAs (rncRNAs), such as microRNA (miRNA), piwi-interacting RNA (piRNA), competing endogenous RNA (ceRNA), long non-coding RNA (lncRNA) and many more. Our group is composed of molecular biologists as well as bioinformaticists. We are applying next generation sequencing (NGS), microarray and molecular biology tools to decrypt roles played by these rncRNAs in stem cell pluripotency and differentiation as well as in diseases such as cancer and neurodegenerative diseases.

Our research is being supported and sponsored by various national funding agencies of Govt. of India, such as DST (Dept. of Science & Technology), DBT (Dept. of Biotechnology), CSIR (Council of Scientific & Industrial Research) etc.

Regulatory non-coding RNAs (rncRNAs) and epigenetic interplay in breast and ovarian cancer
It is now believed that rncRNAs, such as miRNAs, lncRNAs and piRNAs are promising rheostats of gene regulation as they target a significant fraction of genes in a genome. The dysregulation of these rncRNAs are associated with cellular dysfunctions leading to diseases, such as cancers, neurodegenerative diseases and many more. Moreover, some of these rncRNAs are reported to function as oncogenes or tumor suppressor genes. Seeing the differential characteristic expression patterns of mRNAs as well as rncRNAs in carcinomas, such as breast cancer and ovarian cancer (two major female cancers), we propose that the interplay between genes/mRNAs and epigenetic events (DNA hyper/hypo- methylation and histone modifications) or genes/mRNAs and rncRNAs (miRNAs/piRNAs) might be playing a major role in the initiation and metastatic spread of these females malignancies. Breast cancer is the most commonly diagnosed cancer in women, whereas ovarian cancer is less common, but the fifth most lethal cancer in women as it’s symptoms are obscure which make it much harder to detect this gynaecological cancer. Seeing the lethality of these cancers, our lab is focussed to identify genomic and epigenomic hub operating in these two female malignancies to bridge the gap of understanding of regulation at molecular level with an aim to develop rncRNA-based therapeutics and diagnostic markers for these two cancers. Investigations are underway to decrypt the roles of rncRNAs and epigenetic events (hyper/hypo- methylation) in understanding the oncogenetic/metastatic events in these two malignancies by integrating expression profiling and analysis, next-generation sequencing, target analysis (reporter assays), methylation studies (bisulfite sequencing) and inhibition/over-expression studies in cell lines to identify potential rncRNA-biomarkers, especially piRNA biomarkers and predict key epigenome–rncRNA-mRNA regulatory circuits responsible for malignant growth or metastasis which in turn might help in diagnosis and treatment of these female cancers.

Impact of SNPs on miRNA-mediated regulation in cancer and neurodegenerative diseases

Several GWAS studies have reported single nucleotide polymorphisms (SNPs) or INDELs to be associated with susceptibility of diseases, such as cancer (breast cancer, ovarian cancer) as well as neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease). The underlying mechanisms of disease associations are generally explained for non-synonymous SNPs present within coding regions of the genes. However, roles of SNPs that are present elsewhere (5’UTR, 3’UTR) in the genome, but found to be associated with these diseases remain largely unknown. It is well known that miRNAs target mostly 3’UTR and rarely 5’UTR of mRNAs through complementary base pairing with 2-7/8 nts of miRNA and regulate expression of corresponding target mRNAs. Therefore, mutations/SNPs reported in 3’UTR and 5’UTR of the genes associated with above diseases might lead to creation of new target sites or destruction of target sites for miRNAs differentially expressed in these diseases. This will help in understanding aetiology of diseases through impact of SNPs located elsewhere in the genome other than coding regions. Two parallel studies are on-going in our lab to decipher miRNA-mediated regulations interfered by the presence of SNPs and their functional consequence in cancers (breast cancer, ovarian cancer) and neurodegenerative diseases.

Zooming into the dominant microRNA-mediated pluripotency networks in Stem Cells

Besides malignancies, miRNAs have been found to have critical roles in self-renewal, pluripotency and differentiation of embryonic stem cells (ESCs). Some miRNAs promote self-renewal and antagonizes differentiation, whereas others promote differentiation. Furthermore, ESCs are powerful tools for regenerative medicine, but pose ethical concerns. To overcome this ethical concerns, iPSCs (induced pluripotent stem cells) are generated from differentiated human and mouse adult somatic cells through reprogramming by employing many elegant approaches using transcription factors (TFs) (comprising Oct4, Sox2, Nanog, Klf4, Lin28 and c-Myc) as an alternative to ESCs for regenerative therapy. However, this approach shows low reprogramming efficiency which becomes a major bottleneck for therapeutic use.
        To enhance the efficiency of induced pluripotency and cellular reprogramming, few recent classical studies exploited the regulatory potential of miRNAs and used different sets of ESC-specific miRNAs to successfully generate mi-iPSCs. These studies reported that the efficiency of their approach is more efficient, roughly about two orders of magnitude than the reprogramming by TFs. This implies there are a lot of rooms for enhancing the efficiency of reprogramming using miRNAs or combination of miRNAs and TFs. This inefficiency is because of incomplete understanding and gap of knowledge related to stem cell pluripotency and differentiation networks/processes. Therefore, we are zooming into microRNA-mediated pluripotency networks in-depth integrating ChIP-seq, microarray, methyl-seq, regulatory network analysis and other molecular approaches. This will enable us to understand stem cell pluripotency regulatory circuits/events(genetic/epigenetic) in-depth and discover novel miRNA-cocktails that can collectively regulate the entire core pathways and pluripotency networks and induce cellular reprogramming more efficiently than the earlier methods to generate safe mi-iPSCs for personalized regenerative therapy.

Metastatic cascades/potential of tumors of epithelial and mesenchymal tissues of origin
The metastasis cascades in two classes of cancers; (a) cancer of epithelial tissues (referred to as carcinoma) and cancers of mesenchymal tissues (referred to as sarcoma) that are classified according to the International Classification of Diseases for oncology, third edition (ICD-O-3) is one of prime focus of our lab. We know that all cancers share the common principles of malignancies, however individual classes of tumors differ in their particular specificities of the complex multistep hallmarks of malignant growth including metastasis, one of the major event leading to lethality and invasiveness of the malignancies. Metastasis process in carcinoma is comparatively well studied; however it is largely unknown in sarcoma/soft tissue sarcoma (STS).
        STS are a heterogeneous group of highly malignant tumors originated in mesenchymal tissues and are divided into more than fifty subtypes. These are reported to possess high metastatic potential, but only approximately 1% of these malignancies are diagnosed. Due to their rarity, the oncogenesis, especially metastasis of STS and critical regulators of this hallmark is poorly deciphered. Therefore, we are focussed on determining the genetic and epigenetic networks/factors (miRNAs/TFs/mRNAs) modulating metastasis in STS and how metastatic cascade is different in carcinomas which account for approx 90% of cancers. Moreover, we wish to find out which one these cancer types possess more metastatic potential and what are the underlying features/factors/mechanisms contributing to this.

 

Above research themes are just glimpse of focus of our RNAi lab, but not limited to only these. Other projects will be updated in due course.