Elizalde, M. (María)
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- Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4α degradation, preserving hepatic differentiation and protecting from liver damage(Wiley, 2021) Latasa, M.U. (María Ujué); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Pineda-Lucena, A. (Antonio); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); García-Ruiz, C. (Carmen); Azkona, M.T. (María Teresa); Sangro, B. (Bruno); Fernández-Checa, J.C. (José C.); Esquivel, A. (Argitxu); Raquel; Recalde, M. (Miriam); Gárate-Rascón, M. (María); García-Fernández-de-Barrena, M. (Maite); Elizalde, M. (María); Bilbao, I. (Idoia); Jiménez-Andrés, M. (Maddalen)Background and aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7+/- ) mice undergoing chronic (CCl4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4 -injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/- mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
- Splicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteins(Oxford University Press (OUP), 2019) Latasa, M.U. (María Ujué); Berasain, C. (Carmen); Arechederra, M. (María); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Rodriguez-Ortigosa, C.M. (Carlos M.); Azkona, M.T. (María Teresa); Sangro, B. (Bruno); Santamaría, E. (Eva); Alignani, D. (Diego); Raquel; Álvarez-Sola, G. (Gloria); Colyn, L. (Leticia); García-Fernández-de-Barrena, M. (Maite); Elizalde, M. (María); Bárcena-Varela, M. (Marina); Jiménez-Andrés, M. (Maddalen)Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA–DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
- Splicing regulator SLU7 is essential for maintaining liver homeostasis(2014) Latasa, M.U. (María Ujué); Berasain, C. (Carmen); Collantes, M. (María); García-Irigoyen, O. (Oihane); Uriarte, I. (Iker); Avila, M.A. (Matías Antonio); Azkona, M.T. (María Teresa); Goñi, S. (Saioa); Raquel; Prieto, J. (Jesús); Lujambio, A. (Amaya); Elizalde, M. (María); Segura, V. (Víctor); Scala, M. (Marianna) DiA 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.
- Estudio del papel fisiopatológico de Slu7 en el hígado(Servicio de Publicaciones de la Universidad de Navarra, 2014) Elizalde, M. (María); Berasain, C. (Carmen); Avila, M.A. (Matías Antonio)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.