Splicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death

Abstract

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.

The Genome of the Blue Death-Feigning Beetle, Asbolus verrucosus Leconte, 1851 (Coleoptera: Tenebrionidae)

“…Other genes involved in genome maintenance are less well characterized, but their loss results in increased DNA damage signaling (mitogen-activated protein kinase binding protein 1), chromosome loss (kinesin family member C1), or increased DNA double-strand breaks (serine/arginine-rich splicing factor 1) (Leva et al 2012; Macia et al 2017; Wei and Yang 2019). Srsf1 is proposed to function in genome maintenance by removing RNA-DNA hybrids that cause double-strand breaks (Arif et al 2023; Leva et al 2012).…”

Emerging roles of RNA‐binding proteins in fatty liver disease

“…More recently, an additional role for SRSF1 in preventing the formation of deleterious R‐loops in hepatocytes was discovered. SRSF1‐knockout hepatocytes exhibit excessive R‐loop formation leading to lipid accumulation, necroptotic cell death, inflammation, and fibrosis, resulting in spontaneous non‐alcoholic steatohepatitis‐like liver pathology (Arif et al, 2023).…”

“…Many pathological outcomes linked to R‐loops involve dysregulation in R‐loop formation (Arif et al, 2023; Bonnet et al, 2017; Jiménez et al, 2019; Shih et al, 2022) and removal (Cohen et al, 2018; Zhao et al, 2022) at sites associated with DNA break and/or repair. Splicing regulator SLU7 has been shown to prevent R‐loop formation directly as well as by promoting transcription of a full‐length splicing factor belonging to the SR protein family, SRSF3, in hepatocytes.…”

Alternative splicing and related RNA binding proteins in human health and disease

“…In mice with targeted SRSF1 deficiency, acute liver injury is associated with excessive formation of harmful RNA-DNA hybrids (R-loops), which induces DNA damage and further leads to genomic changes in hepatocytes, metabolic disorders, and acute liver injury. 109 Besides, SRSF3 is necessary for hepatocyte differentiation, 110 SRSF10 is involved in regulating fat formation and obesity, and SLU7 is necessary for liver homeostasis. 111 Recent research has highlighted that the postnatal remodeling and maturation of the liver are driven by coordinated changes in celltype-specific transcription and post-transcription.…”