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Research

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Team

Alumni

Rakesh S. Laishram, PhD

Scientist E1 and Wellcome Trust - IA Intermediate fellow

(O) +91-471-2529592
(M) +91-9567667092

laishram@rgcb.res.in

Rakesh_Laishram
Rakesh_Laishram

Rakesh S. Laishram, PhD

Scientist E1 and Wellcome Trust - IA Intermediate fellow

(O) +91-471-2529592
(M) +91-9567667092

laishram@rgcb.res.in

  • Profile

    • Ph.D. Molecular Biology/Biochemistry, Centre for DNA Fingerprinting and Diagnostics, Hyderabad – 2008
    • M.Sc. Biosciences, JamiaMilliaIslamia, New Delhi – 2003
    • B.Sc. Chemistry (Hons), Manipur University – 2001
    • July 2015, Scientist E1, and Wellcome Trust-India Alliance Intermediate Fellow, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
    • July 2012, Scientist C and Wellcome Trust-India Alliance Intermediate Fellow, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India
    • March - August 2013, Visiting Associate Scientist, University of Wisconsin-Madison USA
    • February 2008 - June 2012, Research Associate, University of Wisconsin-Madison, USA
    • Wellcome Trust (UK) - India Alliance Intermediate Fellowship - 2012
    • American Heart Association Scientist Development Award/Grant, USA - 2012
    • Innovative Young Biotechnologist Award (IYBA), DBT, India - 2012
    • Ramalingaswami Fellowship, Department of Biotechnology, India - 2012
    • American Heart Association Post-doctoral Fellowship, USA - 2009
    • CSIR Junior and Senior Research Fellowships, India 2003 - 2008
    • Invited Graduate Student, Attractive Graduate Student Initiative, Japan - 2006
    • JNCASR Summer Research Fellowship 2002
    • Gold Medal in Chemistry 2001, Manipur University
    • American Heart Association
    • “Faculty of 1000-Biology” – Associate faculty member
    • Indian National Science Congress Association
  • Research

    mRNA UTR processing and non-coding RNAs: Specificity and cellular implications in diseases

    All eukaryotic mRNAs (except those encoding histones) harbour poly(A) tail at the 3'-end, which is required for stability and efficient translation. There are two major poly(A) polymerases (PAPs) in the nucleus involved in general mRNA polyadenylation - canonical PAPα/γ and Star-PAP. Interestingly, more than 70% of human genes are alternatively polyadenylated (APA) at the 3'- UTR, encoding multiple mRNA isoforms with different UTR lengths which in turn modulates gene expression. We are interested in understanding the mechanism of PAP specificity, regulation of alternative polyadenylation, and its cellular implications in cardiovascular disease (CVD) and cancer.

    We focus on the non-canonical PAP, Star-PAP that targets mRNA selectively for polyadenylation. We demonstrate PAP sp¬ecificity, where Star-PAP recognises a distinct element and excludes PAPα from the 3'-UTR. Various signalling pathways influence Star-PAP specificity through phosphorylation(s) of Star-PAP and association with unique co-regulators. We identified unique Star-PAP associated factor - RNA binding motif 10 (RBM10) as a regulator of cardiac hypertrophy (CH). In both cellular and animal models for CH, RBM10 and Star-PAP expression is down regulated resulting in reduced expression of anti-hypertrophic genes. In addition, Star-PAP-mediated 3'-end processing acts as a key anti-invasive mechanism in cancer cells that requires the co-regulator PIPKIα. Star-PAP knockdown increases cellular invasiveness in breast carcinoma. These Star-PAP functions are mediated through phosphorylation(s) downstream of signalling pathways, and we identified ~25 such variable phosphorylation events on Star-PAP. Investigation of these signalling pathways and the consequence phosphorylation events will be crucial to understand how Star-PAP regulates cellular functions and outcomes in CVDs and cancer.

  • Publications

    1. Kandala, D., Mohan, N., Vivekakanda, A., Sudheesh, A.P., Reshmi, G., and Rakesh S. Laishram. 2016. CstF and 3'UTR cis-element determine Star-PAP specificity for target mRNA selection by excluding PAPα. Nucleic Acid Res. 44 (2): 811-823.
    2. Mohan, N., Sudheesh A.P., Francis, N., Anderson, R.A. and Rakesh S. Laishram. 2015. Phosphorylation regulates Star-PAP PIPKIα interaction and directs specificity toward mRNA targets. Nucleic Acid Res. 43: 7005-7020.
    3. Rakesh S. Laishram. 2014. Poly(A) Polymerase (PAP) diversity in the cell: Star-PAP vs canonical PAP. FEBS Letters. 588: 2185-2197.
    4. D. Ray, H. Kazan, K. Cook, M. Weirauch, H. N, X. Li, S. G, Albu, H. Zheng, H. Na, M. Irimia, L. Matzat, S. Smith, C. Y, S. K, B. Nabet, Rakesh S. Laishram, M. Qiao H. Lipshitz, F. Piano, A. Yang, A. Corbett, R. Crastens, et. al. 2013. A compendium of RNA-binding motifs for decoding gene regulation. Nature. 499: 172-177
    5. Wiemin Li*, Rakesh S. Laishram*, and Richard A. Anderson. 2013. The novel poly(A) polymerase Star-PAP is a signal-regulated switch at the 3′-end of mRNAs. Adv. Biol. Reg. 53: 64-76. (*First author)
    6. Weimin Li*, Rakesh S. Laishram*, Zhe Ji, Christy A. Barlow, Bin Tian, and Richard A. Anderson. 2012. Star-PAP Control of BIK Expression and Apoptosis is Regulated by Nuclear PIPKI α and PKC δ Signaling. Mol. Cell. 45: 25-37. (*First Author)
    7. Rakesh S. Laishram, Christy A. Barlow, and Richard A. Anderson. 2011. CKI isoforms α and ε regulates Star-PAP target messages by modulating Star-PAP polyadenylation activity. Nucleic Acid Research . 39 (18): 7961-7973.
    8. Rakesh S. Laishram and Richard A. Anderson. 2010. The poly (A) polymerase Star-PAP controls 3’-end cleavage by promoting CPSF interaction with pre-mRNA. EMBO J. 29: 4132-4135. Highlighted by William F Marzluff.The EMBO Journal (2010) 29, 4066-4067.
    9. Christy A Barlow*, Rakesh S Laishram* and Richard A. Anderson. 2010. Nuclear Phosphoinositide signaling - an enigma in compartmental conundrum. Trends in Cell Biol . 20(1): 25-35. (*Equal first author and listed alphabetically)
    10. Rakesh S. Laishram and J. Gowrishankar. 2007. Environmental regulation at the promoter clearance step of bacterial transcription. Genes Dev. 21: 1258-1272
    11. Nandineni, M.R., Rakesh S. Laishram, and J. Gowrishankar. 2004. Osmosensitivity associated with insertions in ArgP (IciA) or glnE in glutamate synthase (GOGAT)-deficient mutants of E. coli. J. Bacteriol. 186:6391-6399
  • Team


    Neelima Singh, Ph.D, Post-Doctoral Fellow

    Cardiac lipid metabolism and its regulation: role of RNA processing and non-coding RNAs:

    Heart balances uptake, metabolism and oxidation of fatty acids to maintain ATP production, membrane biosynthesis and lipid signaling. Under pathological conditions such as obesity, type-2-diabetes, and ageing, cardiac uptake and oxidation of fatty acids are compromised that leads to cardiac lipotoxicity. Lipotoxicity is defined as excess accumulation and over-activation of lipid signaling pathways which trigger cellular dysfunction and death. When this process occurs in cardiomyocytes, the consequences lead to cardiac dysfunction and heart failure. The fatty acid metabolites linked with cardiac lipotoxicity include ceramides, diacylglycerol (DAG), long-chain-acyl-CoAs, acylcarnitines, lysophospholipids and triacylglycerols (TAG). However cardiac lipid metabolism and its regulation are still relatively unexplored. We aim to understand the metabolism and regulation of lipids such as TAG, DAG and phosphatidylinositol (PI) under lipotoxic environment.

    Neelima Singh
    Neelima Singh

    Neelima Singh, Ph.D, Post-Doctoral Fellow

    Cardiac lipid metabolism and its regulation: role of RNA processing and non-coding RNAs:

    Heart balances uptake, metabolism and oxidation of fatty acids to maintain ATP production, membrane biosynthesis and lipid signaling. Under pathological conditions such as obesity, type-2-diabetes, and ageing, cardiac uptake and oxidation of fatty acids are compromised that leads to cardiac lipotoxicity. Lipotoxicity is defined as excess accumulation and over-activation of lipid signaling pathways which trigger cellular dysfunction and death. When this process occurs in cardiomyocytes, the consequences lead to cardiac dysfunction and heart failure. The fatty acid metabolites linked with cardiac lipotoxicity include ceramides, diacylglycerol (DAG), long-chain-acyl-CoAs, acylcarnitines, lysophospholipids and triacylglycerols (TAG). However cardiac lipid metabolism and its regulation are still relatively unexplored. We aim to understand the metabolism and regulation of lipids such as TAG, DAG and phosphatidylinositol (PI) under lipotoxic environment.

    Poulami Basu, Ph.D, Post-Doctoral Fellow

    Role of small non-coding RNAs and RNA processing factors in Gestational Diabetes:

    Gestational Diabetes mellitus (GDM) is a common complication in pregnancy that affects 6-7% of all pregnancies worldwide. GDM is diagnosed in the last trimester of pregnancy when the fetus is already affected by the faulty maternal metabolism, and till date the real cause of GDM is still unknown. I am investigating any mechanistic role of deregulated exosome content and secretion in causing GDM. Currently I am focusing on the exosomal micoRNA and RNA processing factors found in GDM that reaches the target cells and potentially deregulates the protein production and alteration of the downstream pathways leading to GDM. The ultimate goal of my study is to establish exosome as a potential therapeutic agent and putative biomarker for diagnosing GDM in future.

    Poulami Basu
    Poulami Basu

    Poulami Basu, Ph.D, Post-Doctoral Fellow

    Role of small non-coding RNAs and RNA processing factors in Gestational Diabetes:

    Gestational Diabetes mellitus (GDM) is a common complication in pregnancy that affects 6-7% of all pregnancies worldwide. GDM is diagnosed in the last trimester of pregnancy when the fetus is already affected by the faulty maternal metabolism, and till date the real cause of GDM is still unknown. I am investigating any mechanistic role of deregulated exosome content and secretion in causing GDM. Currently I am focusing on the exosomal micoRNA and RNA processing factors found in GDM that reaches the target cells and potentially deregulates the protein production and alteration of the downstream pathways leading to GDM. The ultimate goal of my study is to establish exosome as a potential therapeutic agent and putative biomarker for diagnosing GDM in future.

    Sudheesh AP, M.Sc, SRF

    Role of mRNA 3'-end processing coupled with nuclear phosphoinositide signal in cell invasion and migration:

    Pre-mRNA processing at the 3'-untranslated region (UTR) of mRNA is an essential step in eukaryotic gene expression which results in the generation of a Poly (A) tail. Having a tail at the end provides mRNA it's much needed stability and also influences its translation efficiency. Poly (A) Polymerases or PAPs play an important role in the 3' end processing complex. Star-PAP (Speckle targeted PIPKIα regulated PAP), a nuclear non-canonical PAP carries out polyadenylation of selective set of nuclear mRNAs. Most of the Star-PAP target mRNAs are functionally involved in regulating critical cellular responses like oxidative stress response, DNA damage, apoptosis and cancer. Reports suggests that most of the key oncogenes and tumour suppressors are controlled through their 3'-UTR but, the exact role of pre-mRNA 3'-end processing in cell invasion and migration is still a vague. Cancer cells endure this migration and invasion that allocate them to metastasise to distant organs or tissues and the cellular invasiveness and migratory potential defines the extent of cancer metastasis. In the nucleus there is a distinct Phosphoinositide signalling network that controls varied functions and my work involves defining the mechanistic role of nuclear phosphoinositide signalling coupled with Star-PAP to mediate the 3' end processing controlling cell invasion in cancer cells.

    Sudheesh
    Sudheesh

    Sudheesh AP, M.Sc, SRF

    Role of mRNA 3'-end processing coupled with nuclear phosphoinositide signal in cell invasion and migration:

    Pre-mRNA processing at the 3'-untranslated region (UTR) of mRNA is an essential step in eukaryotic gene expression which results in the generation of a Poly (A) tail. Having a tail at the end provides mRNA it's much needed stability and also influences its translation efficiency. Poly (A) Polymerases or PAPs play an important role in the 3' end processing complex. Star-PAP (Speckle targeted PIPKIα regulated PAP), a nuclear non-canonical PAP carries out polyadenylation of selective set of nuclear mRNAs. Most of the Star-PAP target mRNAs are functionally involved in regulating critical cellular responses like oxidative stress response, DNA damage, apoptosis and cancer. Reports suggests that most of the key oncogenes and tumour suppressors are controlled through their 3'-UTR but, the exact role of pre-mRNA 3'-end processing in cell invasion and migration is still a vague. Cancer cells endure this migration and invasion that allocate them to metastasise to distant organs or tissues and the cellular invasiveness and migratory potential defines the extent of cancer metastasis. In the nucleus there is a distinct Phosphoinositide signalling network that controls varied functions and my work involves defining the mechanistic role of nuclear phosphoinositide signalling coupled with Star-PAP to mediate the 3' end processing controlling cell invasion in cancer cells.

    Nimmy Mohan, M.Tech, CSIR SRF

    Role of RNA binding protein, RBM10 in gene expression and cardiovascular functions

    RBM10 is a nuclear RNA binding protein which regulates the alternative splicing of apoptotic genes. So far, significance of RBM10 in mRNA processing has not been studied well. We identified RBM10 as a unique Star-PAP co-regulator through mass spectrometry sequencing and discovered that RBM10 regulates the 3'end processing of cardiac mRNAs. Currently, we are studying the signalling pathway involved in the regulation of cardiac hypertrophy mediated by RBM10. We are also investigating the post-translational modification such as phosphorylation in RBM10 in the regulation of target gene expression and its function.

    NimmyMohan
    NimmyMohan

    Nimmy Mohan, M.Tech, CSIR SRF

    Role of RNA binding protein, RBM10 in gene expression and cardiovascular functions

    RBM10 is a nuclear RNA binding protein which regulates the alternative splicing of apoptotic genes. So far, significance of RBM10 in mRNA processing has not been studied well. We identified RBM10 as a unique Star-PAP co-regulator through mass spectrometry sequencing and discovered that RBM10 regulates the 3'end processing of cardiac mRNAs. Currently, we are studying the signalling pathway involved in the regulation of cardiac hypertrophy mediated by RBM10. We are also investigating the post-translational modification such as phosphorylation in RBM10 in the regulation of target gene expression and its function.

    Nimmy Francis, M.Sc, SRF

    Linking the two (A) tails: role of polyadenylation in bacterial mRNA expression

    Polyadenylation is the addition of long adenosine nucleotides at the mRNA 3'-end in a template independent manner by enzymes called poly (A) polymerases (PAPs). Bacterial poly (A) tail is short in length (60-80 adenosines) and adenylation is done by bacterial enzyme PAPI. Poly (A) tails recruits degradosome complex (PNPase, RNA helicase and RNase E) in bacteria, associates with another poly (A) binding protein (PABP) in eukaryotes and stabilizes the mRNA. However, the exact mechanism for the functional difference is not known. Therefore, we concentrate to define the basic mechanisms of mRNA stability between the two organisms and precisely determine what links the two polyadenylation and stabilization mechanisms. We hypothesize that PABP is the factor that links both polyadenylation mechanisms. Hence we used trans-expression of mammalian nuclear poly (A) binding protein (PABP) as main strategy to study the significance of stability of poly (A) tailed mRNA in bacteria. My work focuses on the role of mRNA stabilization under certain physiological conditions like stress response, pathogenesis and other metabolic pathways through post transcriptional polyadenylation.

    NimmyFrancis
    NimmyFrancis

    Nimmy Francis, M.Sc, SRF

    Linking the two (A) tails: role of polyadenylation in bacterial mRNA expression

    Polyadenylation is the addition of long adenosine nucleotides at the mRNA 3'-end in a template independent manner by enzymes called poly (A) polymerases (PAPs). Bacterial poly (A) tail is short in length (60-80 adenosines) and adenylation is done by bacterial enzyme PAPI. Poly (A) tails recruits degradosome complex (PNPase, RNA helicase and RNase E) in bacteria, associates with another poly (A) binding protein (PABP) in eukaryotes and stabilizes the mRNA. However, the exact mechanism for the functional difference is not known. Therefore, we concentrate to define the basic mechanisms of mRNA stability between the two organisms and precisely determine what links the two polyadenylation and stabilization mechanisms. We hypothesize that PABP is the factor that links both polyadenylation mechanisms. Hence we used trans-expression of mammalian nuclear poly (A) binding protein (PABP) as main strategy to study the significance of stability of poly (A) tailed mRNA in bacteria. My work focuses on the role of mRNA stabilization under certain physiological conditions like stress response, pathogenesis and other metabolic pathways through post transcriptional polyadenylation.

    Ganesh Ram Koshre, M.Sc, JRF

    Post translational modifications and signalling regulation of Star-PAP and its cellular implications:

    Star-PAP, a nuclear non-canonical Poly (A) polymerase is regulated by different signalling molecules such as CKIα and PKCδ to process select set of mRNA targets. We observed Star-PAP functional switch under different signaling conditions in the cell. I am trying to define the mechanism of this functional switch and one such mechanism is the differential phosphorylation status on Star-PAP and its regulation by various signalling pathways. My work involves understanding the signal mediated regulation of Star-PAP in carrying out 3’end processing of mRNAs under different physiological stress conditions and how it is implicated in different cellular functions and diseases.

    ganesh
    ganesh

    Ganesh Ram Koshre, M.Sc, JRF

    Post translational modifications and signalling regulation of Star-PAP and its cellular implications:

    Star-PAP, a nuclear non-canonical Poly (A) polymerase is regulated by different signalling molecules such as CKIα and PKCδ to process select set of mRNA targets. We observed Star-PAP functional switch under different signaling conditions in the cell. I am trying to define the mechanism of this functional switch and one such mechanism is the differential phosphorylation status on Star-PAP and its regulation by various signalling pathways. My work involves understanding the signal mediated regulation of Star-PAP in carrying out 3’end processing of mRNAs under different physiological stress conditions and how it is implicated in different cellular functions and diseases.

    Jinisha Jagan Jacob, M.Sc, JRF

    Role of RNA processing factors in eukaryotic cell cycle regulation

    Cell cycle control system is complex machinery involving large number of proteins that performs each events of the cell cycle with astonishing speed and accuracy. Various extracellular and intracellular signals regulate progression of cell cycle from one phase to another. Studies have revealed important cell cycle -specific effects of PKC signalling that can either positively or negatively impact proliferation. The direct interaction of PKCδ with PIPKI α has been reported. Star- PAP, a non-canonical PAP was identified as an interacting partner of PIPKIα and is one of the direct substrates of PKCδ. PKCδ regulated Star-PAP control in BIK expression and induction of apoptosis has been extensively studied. However, what is unknown is how Star-PAP and other RNA processing factors regulate cell cycle, what are its direct and indirect targets. I´m trying to understand how nexus of poly (A) polymerase and other processing factors regulate the cell cycle control system and determine the cell fate.

    jinisha
    jinisha

    Jinisha Jagan Jacob, M.Sc, JRF

    Role of RNA processing factors in eukaryotic cell cycle regulation

    Cell cycle control system is complex machinery involving large number of proteins that performs each events of the cell cycle with astonishing speed and accuracy. Various extracellular and intracellular signals regulate progression of cell cycle from one phase to another. Studies have revealed important cell cycle -specific effects of PKC signalling that can either positively or negatively impact proliferation. The direct interaction of PKCδ with PIPKI α has been reported. Star- PAP, a non-canonical PAP was identified as an interacting partner of PIPKIα and is one of the direct substrates of PKCδ. PKCδ regulated Star-PAP control in BIK expression and induction of apoptosis has been extensively studied. However, what is unknown is how Star-PAP and other RNA processing factors regulate cell cycle, what are its direct and indirect targets. I´m trying to understand how nexus of poly (A) polymerase and other processing factors regulate the cell cycle control system and determine the cell fate.

    Sneha Sandra. P.S, M.Sc, Project Assistant

    Role of poly (A) binding proteins in bacterial mRNA stabilization:

    Polyadenylation is a post-transcriptional regulatory step both in prokaryotes and eukaryotes. While presence of poly (A) tail stabilizes mRNA in eukaryotes, its counterparts marks mRNA for degradation in prokaryotes. It has been known that poly (A) binding proteins stabilizes poly (A) tailed mRNAs in eukaryotes. Hence, we trans-express eukaryotic PABP in bacteria to study the role of PABP in mRNA stabilization. The poly(A) polymerase enzyme, PAPΙ adds poly(A) tail to the 3' end of mRNA in prokaryotes and two types of PAP’s were reported earlier. The key PAP is encoded by pcnB gene and is known to polyadenylate selected mRNAs. However, our RNA-seq data shows differential upregulation of mRNAs on PABP trans-expression compared to pcnB mutation. We investigate possible role of secondary PAP in polyadenylation and mRNA stabilization in conjunction with poly (A) binding proteins.

    NimmyMohan
    NimmyMohan

    Sneha Sandra. P.S, M.Sc, Project Assistant

    Role of poly (A) binding proteins in bacterial mRNA stabilization:

    Polyadenylation is a post-transcriptional regulatory step both in prokaryotes and eukaryotes. While presence of poly (A) tail stabilizes mRNA in eukaryotes, its counterparts marks mRNA for degradation in prokaryotes. It has been known that poly (A) binding proteins stabilizes poly (A) tailed mRNAs in eukaryotes. Hence, we trans-express eukaryotic PABP in bacteria to study the role of PABP in mRNA stabilization. The poly(A) polymerase enzyme, PAPΙ adds poly(A) tail to the 3' end of mRNA in prokaryotes and two types of PAP’s were reported earlier. The key PAP is encoded by pcnB gene and is known to polyadenylate selected mRNAs. However, our RNA-seq data shows differential upregulation of mRNAs on PABP trans-expression compared to pcnB mutation. We investigate possible role of secondary PAP in polyadenylation and mRNA stabilization in conjunction with poly (A) binding proteins.

  • Alumni