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Title:Elucidating the role of SRSF1, a prototypical splicing factor, in liver physiology
Author(s):Arif, Waqar
Director of Research:Kalsotra, Auinash
Doctoral Committee Chair(s):Kalsotra, Auinash
Doctoral Committee Member(s):Huang, Raven H; Prasanth, Kannanganattu V; Zhang, Kai
Department / Program:Biochemistry
Discipline:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):SRSF1
RNA
Splicing
Liver
DNA Damage
Abstract:My thesis focuses on understanding the functional role of SRSF1, a prototypical splicing factor, in the context of liver physiology. I began by generating and characterizing hepatocyte-specific SRSF1 knock-out mice models. These mice developed severe liver damage and exhibited pathology like the human disease Non-alcoholic steatohepatitis. Specifically, loss of SRSF1 results in immediate cell death and triggers a regenerative response in the liver. While SRSF1 was initially discovered as a splicing factor, studies since its discovery has revealed it plays multiple roles in RNA biology. This ranges from mRNA transport, translation regulation, non-sense mediated decay and even processing of miRNA. Therefore, it is not surprising that SRSF1 is vital for the survival of the cell. While deficiency in most tissues results in organ failure, the liver has the remarkable capability to circumvent the Cre-lox based knock-out of SRSF1. However, the chronic cycle of death and regeneration leads to the development of NASH-like pathology. To understand primary changes occurring in the model, an acute SRSF1 knock-out model was developed. Insight into the molecular basis of the pathology was gained using transcriptome- and proteome-wide approaches such as RNA-Seq, eCLIP-Seq, and mass spectrometry. Extensive investigation to the molecular mechanism underlying the pathology revealed loss of SRSF1 activity leads to widespread DNA damage and defects in global translation. With the widespread damage, SRSF1 deficient hepatocytes eventually undergo necroptosis leading to failure of the liver. Moreover, these defects were also observed in siRNA mediated knockdown of SRSF1 in HepG2 cells, a human liver cancer cell line, demonstrating these effects are conserved.
Issue Date:2020-12-03
Type:Thesis
URI:http://hdl.handle.net/2142/109421
Rights Information:Copyright 2020 Waqar Arif
Date Available in IDEALS:2021-03-05
Date Deposited:2020-12


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