Elucidating the role of SRSF1, a prototypical splicing factor, in liver physiology

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2021

Author dc:creator

• Arif, Waqar

Contributors dc:contributor

• Kalsotra, Auinash
• Huang, Raven H
• Prasanth, Kannanganattu V
• Zhang, Kai

• SRSF1
• RNA
• Splicing
• Liver
• DNA Damage

Statement dc:rights

• Copyright 2020 Waqar Arif

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/109421

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/109421