Slu7-KO Mouse

SLU7, also known as Splicing factor synergistic lethal with U5 snRNA 7, is a crucial factor in gene expression regulation. Initially identified as a splicing factor essential for proper 3' splice site selection, it significantly impacts gene transcript diversity. It also serves as an integrative hub for multiple levels of gene expression regulation, including epigenetic DNA remodeling, transcription modulation, and protein stability. These regulatory functions are vital for cellular processes such as liver differentiation, genome integrity maintenance, and correct cell cycle progression [1].

In animal models of liver injury and human HCC, the process of nonsense-mediated RNA decay (NMD) is inhibited. The splicing factor SLU7 interacts with and preserves the levels of the NMD effector UPF1, and SLU7 is required for correct NMD. Caspases activated during liver damage are responsible for the cleavage and degradation of SLU7, which contributes to the malignant reshaping of the liver transcriptome [2]. In Slu7-haploinsufficient/heterozygous (Slu7+/- ) mice, reduced SLU7 expression leads to a switch in HNF4α promoter usage, increased sensitivity to liver injury, enhanced oxidative stress, and impaired hepatic functions. Restoring SLU7 expression using AAV-SLU7 prevents liver injury and hepatocellular dedifferentiation [3]. SLU7 knockdown in human liver cells and mouse liver results in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and a fetal-like gene expression pattern. It also increases hepatocellular proliferation and induces a tumor-like glycolytic phenotype [4].

In conclusion, SLU7 is a central regulator of gene expression, playing essential roles in maintaining cellular functions such as liver homeostasis, genome integrity, and cell cycle progression. Studies using gene knockout or conditional knockout mouse models have revealed its significance in liver-related diseases, including hepatocellular carcinoma and liver injury, highlighting its potential as a therapeutic target.

References:

1. Gárate-Rascón, María, Recalde, Miriam, Rojo, Carla, Arechederra, María, Berasain, Carmen. 2022. SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease. In International journal of molecular sciences, 23, . doi:10.3390/ijms232113411. https://pubmed.ncbi.nlm.nih.gov/36362191/

2. Rojo, Carla, Gárate-Rascón, María, Recalde, Miriam, Arechederra, María, Berasain, Carmen. 2024. Caspases compromise SLU7 and UPF1 stability and NMD activity during hepatocarcinogenesis. In JHEP reports : innovation in hepatology, 6, 101118. doi:10.1016/j.jhepr.2024.101118. https://pubmed.ncbi.nlm.nih.gov/39105183/

3. Gárate-Rascón, María, Recalde, Miriam, Jimenez, Maddalen, Arechederra, María, Berasain, Carmen. 2021. Splicing Factor SLU7 Prevents Oxidative Stress-Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage. In Hepatology (Baltimore, Md.), 74, 2791-2807. doi:10.1002/hep.32029. https://pubmed.ncbi.nlm.nih.gov/34170569/

4. Elizalde, María, Urtasun, Raquel, Azkona, María, Ávila, Matías A, Berasain, Carmen. 2014. Splicing regulator SLU7 is essential for maintaining liver homeostasis. In The Journal of clinical investigation, 124, 2909-20. doi:10.1172/JCI74382. https://pubmed.ncbi.nlm.nih.gov/24865429/