Sancho-Bru, P. (Pau)
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- Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis(Springer Science and Business Media LLC, 2019) Latasa, M.U. (María Ujué); Blokhin, I.O. (Ilya O.); Monga, S.P. (Satdarshan P.); Dubuquoy, L. (Laurent); Berasain, C. (Carmen); Lozano, J.J. (Juan J.); Morgan, M.Y. (Marsha Y.); Vernetti, L.A. (Lawrence A.); Sancho-Bru, P. (Pau); Altamirano, J. (Jose); Wahlestedt, C. (Claes); Fondevilla, C. (Constantino); Gómez, J.L. (Juan L.); Arab, J.P. (Juan P.); Thursz, M.R. (Mark R.); Cao, S. (Sheng); Avila, M.A. (Matías Antonio); Atkinson, S.R. (Stephen R.); Rusyn, I. (Ivan); Edmunds, L.R. (Lia R.); Cabezas, J. (Joaquín); Furuya, S. (Shinji); Bell, A. (Aaron); Aragón, T. (Tomás); Mann, J. (Jelena); Shah, V.H. (Vijay H.); Jurczak, M.J. (Michael J.); Louvet, A. (Alexandre); Taylor, D.L. (D. Lansing); Lackner, C. (Carolin); Bataller, R. (Ramón); Odena, G. (Gemma); Caballeria, J. (Juan); Stärkel, P. (Peter); Gue, J.P. (Joel P.); Ventura-Cots, M. (Meritxell); Argemí, J. (Josepmaria); Mathurin, P. (Philippe); Massey, V. (Veronica); Van-Booven, D. (Derek)Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
- Identification and experimental validation of druggable epigenetic targets in hepatoblastoma(Elsevier, 2023) Indersie, E. (Emilie); Latasa, M.U. (María Ujué); Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Domingo-Sàbat, M. (Montserrat); Pineda-Lucena, A. (Antonio); Sancho-Bru, P. (Pau); Zanatto, L. (Laura); Armengol, C. (Carolina); Uriarte, I. (Iker); Ciordia, S. (Sergio); Avila, M.A. (Matías Antonio); Alaggio, R. (Rita); Alonso, C. (Cristina); Sangro, B. (Bruno); García-Fernandez-Barrena, M. (Maite); Herranz, J.M. (José M.); Cairo, S. (Stefano); García-Marin, J.J. (Jose Juan); Francalanci, P. (Paola); Prosper-Cardoso, F. (Felipe); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Zucman-Rossi, J. (Jessica)Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of b-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.
- Integrated multiomics reveals glucose use reprogramming and identifies a novel hexokinase in alcoholic hepatitis(Baltimore, 2021) Massey, V. (Veronica); Parrish, A. (Austin); Argemí, J. (Josepmaria); Moreno, M. (Montserrat); Mello, A. (Aline); García-Rocha, M. (Mar); Altamirano, J. (Jose); Odena, G. (Gemma); Dubuquoy, L. (Laurent); Louvet, A. (Alexandre); Martínez, C. (Carlos); Adrover, A. (Anna); Affò, S. (Silvia); Morales-Ibanez, O. (Oriol); Sancho-Bru, P. (Pau); García-Millán, C. (Cristina); Alvarado-Tapias, E. (Edilmar); Morales-Arráez, D. (Dalia); Caballeria, J. (Juan); Mann, J. (Jelena); Cao, S. (Sheng); Sun, Z. (Zhaoli); Shah, V.H. (Vijay H.); Cameron, A. (Andrew); Mathurin, P. (Philippe); Snider, N. (Natasha); Villanueva, C. (Càndid); Morgan, T.R. (Timothy R.); Guinovart, J. (Joan); Vadigepalli, R. (Rajanikanth); Bataller, R. (Ramón)Background & aims: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism. Methods: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. Results: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes. Conclusions: Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.