title: Splicing regulator SLU7 is essential for maintaining liver homeostasis.
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.forename: María
authors.initials: M
authors.lastname: Elizalde
authors.forename: Raquel
authors.initials: R
authors.lastname: Urtasun
authors.forename: María
authors.initials: M
authors.lastname: Azkona
authors.forename: María U
authors.initials: MU
authors.lastname: Latasa
authors.forename: Saioa
authors.initials: S
authors.lastname: Goñi
authors.forename: Oihane
authors.initials: O
authors.lastname: García-Irigoyen
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.forename: María
authors.initials: M
authors.lastname: Collantes
authors.forename: Mariana
authors.initials: M
authors.lastname: Di Scala
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Matías A
authors.initials: MA
authors.lastname: Ávila
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D002454:Cell Differentiation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D017411:Ribonucleoproteins, Small Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000072260:RNA Splicing Factors; D017411:Ribonucleoproteins, Small Nuclear; C490656:SLU7 protein, human; C000592060:SLU7 protein, mouse; D014157:Transcription Factors; D005947:Glucose