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Research Interests
Study of the molecular mechanisms of alternative splicing. Investigation of splicing regulation by the epithelial-specific splicing factors Esrp1 and Esrp2 during development and disease. Regulation of genome-wide changes in splicing during the epithelial-mesenchymal transition (EMT).
Key words: Alternative splicing, Post-transcriptional gene regulation, Epithelial Splicing Regulatory Proteins (ESRPs), Epithelial Mesenchymal Transition (EMT).
Description of Research
The focus of my laboratory is investigation of alternative splicing, whereby a single gene transcript can generate numerous spliced mRNAs, thereby greatly expanding ribonomic and proteomic diversity. Our previous studies focused on alternative splicing of fibroblast growth factor receptor 2 (FGFR2) as a model system. Mutually exclusive splicing of two exons, IIIb and IIIc, gives rise to two functionally different receptors, FGFR2-IIIb and FGFR2-IIIc, in epithelial and mesenchymal cells, respectively. The exquisite cell type-specific expression of these epithelial or mesenchymal specific splice variants is essential during vertebrate development. We identified Epithelial Splicing Proteins 1 and 2 (ESRP1 and ESRP2) in a genome-wide screen for FGFR2 splicing regulators. Subsequent work using RNA-Seq and other systems biology approaches has shown that the ESRPs regulate global programs of alternative splicing to enforce an epithelial cell specific splicing network. We are continuing further investigations into the molecular mechanisms by which the ESRPs regulate alternative splicing. To define the role that the Esrps play in mammalian development we generated mice carrying conditional and/or germline knockout alleles for Esrp1 and Esrp2. Esrp1 knockout (KO) mice displayed bilateral cleft lip associated with cleft palate (CL/P), indicating that it is crucial for normal facial development. Mice with combined KO of both Esrp1 and Esrp2 displayed broader defects in organogenesis. We also determined that conditional ablation of Esrp1 and Esrp2 was associated with an epidermal barrier defect due in part to defects in epithelial cell adhesion and tight junction function. Ongoing studies with these mouse models are using a combination of genetics, developmental biology, and systems biology approaches to understand the mechanisms by which the Esrps function to maintain normal mammalian development and how disruption of Esrp function contributes to disease.
Study of the molecular mechanisms of alternative splicing. Investigation of splicing regulation by the epithelial-specific splicing factors Esrp1 and Esrp2 during development and disease. Regulation of genome-wide changes in splicing during the epithelial-mesenchymal transition (EMT).
Key words: Alternative splicing, Post-transcriptional gene regulation, Epithelial Splicing Regulatory Proteins (ESRPs), Epithelial Mesenchymal Transition (EMT).
Description of Research
The focus of my laboratory is investigation of alternative splicing, whereby a single gene transcript can generate numerous spliced mRNAs, thereby greatly expanding ribonomic and proteomic diversity. Our previous studies focused on alternative splicing of fibroblast growth factor receptor 2 (FGFR2) as a model system. Mutually exclusive splicing of two exons, IIIb and IIIc, gives rise to two functionally different receptors, FGFR2-IIIb and FGFR2-IIIc, in epithelial and mesenchymal cells, respectively. The exquisite cell type-specific expression of these epithelial or mesenchymal specific splice variants is essential during vertebrate development. We identified Epithelial Splicing Proteins 1 and 2 (ESRP1 and ESRP2) in a genome-wide screen for FGFR2 splicing regulators. Subsequent work using RNA-Seq and other systems biology approaches has shown that the ESRPs regulate global programs of alternative splicing to enforce an epithelial cell specific splicing network. We are continuing further investigations into the molecular mechanisms by which the ESRPs regulate alternative splicing. To define the role that the Esrps play in mammalian development we generated mice carrying conditional and/or germline knockout alleles for Esrp1 and Esrp2. Esrp1 knockout (KO) mice displayed bilateral cleft lip associated with cleft palate (CL/P), indicating that it is crucial for normal facial development. Mice with combined KO of both Esrp1 and Esrp2 displayed broader defects in organogenesis. We also determined that conditional ablation of Esrp1 and Esrp2 was associated with an epidermal barrier defect due in part to defects in epithelial cell adhesion and tight junction function. Ongoing studies with these mouse models are using a combination of genetics, developmental biology, and systems biology approaches to understand the mechanisms by which the Esrps function to maintain normal mammalian development and how disruption of Esrp function contributes to disease.
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Sushant Bangru, Jackie Chen, Nicholas Baker, Diptatanu Das, Ullas V Chembazhi, Jessica M Derham,Sandip Chorghade,Waqar Arif,Frances Alencastro,Andrew W Duncan,Russ P Carstens,Auinash Kalsotra
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SSRN Electronic Journal (2021)
crossref(2020)
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bioRxiv (Cold Spring Harbor Laboratory)pp.1-37, (2020)
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