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Splicing regulator SLU7 is essential for maintaining liver homeostasis
María Elizalde, … , Matías A. Ávila, Carmen Berasain
María Elizalde, … , Matías A. Ávila, Carmen Berasain
Published May 27, 2014
Citation Information: J Clin Invest. 2014;124(7):2909-2920. https://doi.org/10.1172/JCI74382.
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Research Article Hepatology

Splicing regulator SLU7 is essential for maintaining liver homeostasis

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Abstract

A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.

Authors

María Elizalde, Raquel Urtasun, María Azkona, María U. Latasa, Saioa Goñi, Oihane García-Irigoyen, Iker Uriarte, Victor Segura, María Collantes, Mariana Di Scala, Amaia Lujambio, Jesús Prieto, Matías A. Ávila, Carmen Berasain

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Figure 1

SLU7 strongly influences the gene expression profile of human liver cell lines and modulates SRSF3 splicing.

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SLU7 strongly influences the gene expression profile of human liver cel...
(A and B) Top categories of genes undergoing changes in (A) splicing events and (B) expression in PLC/PRF/5 cells induced by SLU7 knockdown, classified in pathways according to Ingenuity Pathway Analysis. (C) SLU7 downregulation affected SRSF3 alternative splicing, promoting the generation of Iso2 targeted for nonsense-mediated decay (NMD). Bottom: Representative gel analyzing SRSF3 Iso1 and Iso2 PCR products in cells transfected with siSLU7 or siGL control. (D) qPCR analysis of SRSF3 Iso2/Iso1 ratio in PLC/PRF/5, HepG2, and Hep3B cells transfected with siGL or siSLU7. Representative Western blots of SLU7 and ACTIN protein levels are also shown. *P < 0.05 vs. siGL. (E and F) qPCR analysis of SRSF3 Iso2/Iso1 ratio (E) in HepaRG cells upon SLU7 knockdown and (F) in untransfected HepaRG cells (Control) or cells transfected with control vector (pEGFP) or SLU7 expression vector (pEGFP-SLU7). Bottom: Representative Western blot analysis of SLU7 and ACTIN protein levels. *P < 0.05 vs. siGL or pEGFP. (G) SRSF3 expression, analyzed by qPCR, in human liver tissues from control, cirrhotic, and HCC tissue samples. (H) Spearman correlation analysis of SLU7 and SRSF3 expression, analyzed by qPCR, in all groups of human liver tissue samples.
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