TY - JOUR
T1 - Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
AU - Arif, Waqar
AU - Mathur, Bhoomika
AU - Saikali, Michael F.
AU - Chembazhi, Ullas V.
AU - Toohill, Katelyn
AU - Song, You Jin
AU - Hao, Qinyu
AU - Karimi, Saman
AU - Blue, Steven M.
AU - Yee, Brian A.
AU - Van Nostrand, Eric L.
AU - Bangru, Sushant
AU - Guzman, Grace
AU - Yeo, Gene W.
AU - Prasanth, Kannanganattu V.
AU - Anakk, Sayeepriyadarshini
AU - Cummins, Carolyn L.
AU - Kalsotra, Auinash
N1 - We thank the members of the Kalsotra and Anakk laboratories for their valuable discussions and comments on the manuscript. This research was supported through the NIH grants R01AA010154, R01HL126845, and R21HD104039 (to A.K.), R01DK113080 (to S.A.), R01GM132458 and R21AG065748, (to K.V.P.), and R01HG004659, U41HG009889 (to G.W.Y.); the William C. Rose Professorship and the Beckman Fellowship from the Center for Advanced Study at the University of Illinois (to A.K.); Natural Sciences and Engineering Research Council of Canada grant RGPIN-2020-07212 (to C.L.C.); Cancer center @ Illinois seed grants (to A.K, K.V.P, and S.A); the American Cancer Society grant RSG ACS132640 (to S.A.); the NSF grant MCB1723008 (to K.V.P.); the NIH pre-doctoral NRSA fellowship F30DK108567 (to W.A.); the NIH Tissue microenvironment training program T32-EB019944 and UIUC Scott Dissertation Fellowship (to S.B.); and the Ontario Graduate Scholarship (to M.F.S.).
PY - 2023/2/9
Y1 - 2023/2/9
N2 - Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.
AB - Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis, illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how the accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver damage.
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U2 - 10.1038/s41467-023-35932-3
DO - 10.1038/s41467-023-35932-3
M3 - Article
C2 - 36759613
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 551
ER -