Mecanismos transcripcionales y epigenéticos de la plasticidad neuronal

Líneas de investigación

Nuestra investigación se centra en los mecanismos moleculares que permiten el aprendizaje, la formación de nuevos recuerdos y otras modificaciones duraderas del comportamiento animal. En concreto, investigamos el papel de determinados factores de transcripción y epigenéticos en esos procesos. También investigamos cómo el mal funcionamiento de estos mecanismos puede dar lugar a patologías del sistema nervioso. Para abordar esas cuestiones usamos una aproximación multidisciplinar que combina estudios de genética, genómica, biología molecular y celular, electrofisiología y conducta animal. Desde el punto de vista metodológico, estamos particularmente interesados en la aplicación de las nuevas tecnologías de edición epigenética y perfilado genómico en el sistema nervioso.

Nuestra investigación actual se centra en las siguientes dos áreas:

• Regulación de la expresión génica dependiente de actividad por mecanismos epigenéticos y transcripcionales: Los modelos celulares actuales para explicar cómo se forman las memorias proponen que los recuerdos están codificados en forma de cambios en la fuerza de conexiones sinápticas específicas. Estos cambios requieren a su vez de cambios en la expresión génica de las neuronas. En el laboratorio, estamos interesados en explorar el papel que juegan en este proceso algunos factores de transcripción regulados por actividad (como CREB y SRF), algunas enzimas epigenéticas (como CBP y p300), y la modificación covalente de histonas y la metilación del DNA.

• Contribución de mecanismos epigenéticos a la patoetiología de la discapacidad intelectual: Investigamos la relación entre fallos en los mecanismos de regulación epigenética y diversos trastornos neurológicos asociados a problemas cognitivos que son hoy en día incurables, tales como el síndrome de Rubinstein-Taybi y la discapacidad intelectual asociada al cromosoma X. Para ello, generamos y caracterizamos modelos murinos de estos trastornos, investigamos las causas moleculares que subyacen a los síntomas y ensayamos nuevas terapias.

Publicaciones relevantes

Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding Fernández-Nogales, M., López-Cascales, M.T., Murcia-Belmonte, V., Escalante, A., Fernández-Albert, J., Muñoz-Viana, R., Barco, A., Herrera, E. Advanced Science 2022 9 (29): art. 2200615 https://doi.org/10.1002/advs.202200615
CBP is required for establishing adaptive gene programs in the adult mouse brain. Lipinski, M.#, Niñerola, S#., Fuentes-Ramos, M., Valor, L.M., del Blanco, B., López-Atalaya, J.P., Barco, A. J Neurosci. 2022 42(42): 7984-8001 https://doi.org/10.1523/JNEUROSCI.0970-22.2022
Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, Rabaneda LG, García-Lira C, Grand T, Briz V, Velasco ER, Andero R, Niñerola S, Barco A, Paoletti P, Wesseling JF, Gardoni F, Tavalin SJ, Perez-Otaño I eLife 2021 10:e71575 https://doi.org/10.7554/eLife.71575
Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis Cid E, Marquez-Galera A, Valero M, Gal B, Medeiros DC, Navarron CM, Ballesteros-Esteban L, Reig-Viader R, Morales AV, Fernandez-Lamo I, Gomez-Dominguez D, Sato M, Hayashi Y, Bayés À, Barco A, Lopez-Atalaya JP, de la Prida LM Cell Rep 2021 35(10):109229 https://doi.org/10.1016/j.celrep.2021.109229
KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain Lipinski M, Muñoz-Viana R, Del Blanco B, Marquez-Galera A, Medrano-Relinque J, Caramés JM, Szczepankiewicz AA, Fernandez-Albert J, Navarrón CM, Olivares R, Wilczyński GM, Canals S, Lopez-Atalaya JP, Barco A Nat Commun 2020 11(1):2588 https://doi.org/10.1038/s41467-020-16246-0
CBP and SRF co-regulate dendritic growth and synaptic maturation Del Blanco B, Guiretti D, Tomasoni R, Lopez-Cascales MT, Muñoz-Viana R, Lipinski M, Scandaglia M, Coca Y, Olivares R, Valor LM, Herrera E, Barco A Cell Death & Differentiation 2019 26(11):2208 https://doi.org/10.1038/s41418-019-0285-x
CBP/p300 in brain development and plasticity: disentangling the KAT’s cradle Lipinski M, Del Blanco B, Barco A Current Opinion in Neurobiology 2019 59:1 https://doi.org/10.1016/j.conb.2019.01.023
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models Hutson TH, Kathe C, Palmisano I, Bartholdi K, Hervera A, De Virgiliis F, McLachlan E, Zhou L, Kong G, Barraud Q, Danzi MC, Medrano-Fernandez A, Lopez-Atalaya JP, Boutillier AL, Sinha SH, Singh AK, Chaturbedy P, Moon LDF, Kundu TK, Bixby JL, Lemmon VP, Barco A, Courtine G, Di Giovanni S Sci Transl Med 2019 11(487):eaaw2064 https://doi.org/10.1126/scitranslmed.aaw2064
Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus Fernandez-Albert J, Lipinski M, Lopez-Cascales MT, Rowley MJ, Martin-Gonzalez AM, Del Blanco B, Corces VG, Barco A Nature Neuroscience 2019 22(10):1718 https://doi.org/10.1038/s41593-019-0476-2

Investigador principal

Angel L. Barco Guerrero

Investigador doctor

Rafael Alcalá Vida

Investigador doctor

Beatriz Del Blanco Pablos

Investigador doctor

Macarena Lorena Herrera

Investigador doctor

Juan Paraiso Luna

Predoctoral / Apoyo investigación

Marta Alaiz Noya

Predoctoral / Apoyo investigación

Isabel Bustos Martínez

Predoctoral / Apoyo investigación

Miguel Fuentes Ramos

Predoctoral / Apoyo investigación

Sergio Niñerola Rives

Técnico

Mirjam Cangonja

Técnico

Roman Olivares Escalona

Técnico

Carina Vanesa Racovac Farinha

Visitantes

Aitana Moreno Beneit

Visitantes

Patricia Torres Raves

Activation-induced chromatin reorganization in neurons depends on HDAC1 activity Grabowska A, Sas-Nowosielska H, Wojtas B, Holm-Kaczmarek D, Januszewicz E, Yushkevich Y, Czaban I, Trzaskoma P, Krawczyk K, Gielniewski B, Martin-Gonzalez A, Filipkowski RK, Olszynski KH, Bernas T, Szczepankiewicz AA, Sliwinska MA, Kanhema T, Bramham CR, Bokota G, Plewczynski D, Wilczynski GM, Magalska A Cell Rep 2022 38(7):110352 https://doi.org/10.1016/j.celrep.2022.110352
Comprehensive expression analysis for the core cell cycle regulators in the chicken embryo reveals novel tissue-specific synexpression groups and similarities and differences with expression in mouse, frog and zebrafish Alaiz Noya M, Berti F, Dietrich S Journal of Anatomy. 2022 241 (1): 42-66 https://doi.org/10.1111/joa.13629
Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding Fernández-Nogales, M., López-Cascales, M.T., Murcia-Belmonte, V., Escalante, A., Fernández-Albert, J., Muñoz-Viana, R., Barco, A., Herrera, E. Advanced Science 2022 9 (29): art. 2200615 https://doi.org/10.1002/advs.202200615
CBP is required for establishing adaptive gene programs in the adult mouse brain. Lipinski, M.#, Niñerola, S#., Fuentes-Ramos, M., Valor, L.M., del Blanco, B., López-Atalaya, J.P., Barco, A. J Neurosci. 2022 42(42): 7984-8001 https://doi.org/10.1523/JNEUROSCI.0970-22.2022
CBP and p300 Jointly Maintain Neural Progenitor Viability but Play Unique Roles in the Differentiation of Neural Lineages. González-Martínez, R., Márquez-Galera, A., Del Blanco, B., López-Atalaya, J.P., Barco, A., Herrera, E. Cells 2022 11(24): 4118 https://doi.org/10.3390/cells11244118
Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, Rabaneda LG, García-Lira C, Grand T, Briz V, Velasco ER, Andero R, Niñerola S, Barco A, Paoletti P, Wesseling JF, Gardoni F, Tavalin SJ, Perez-Otaño I eLife 2021 10:e71575 https://doi.org/10.7554/eLife.71575
Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis Cid E, Marquez-Galera A, Valero M, Gal B, Medeiros DC, Navarron CM, Ballesteros-Esteban L, Reig-Viader R, Morales AV, Fernandez-Lamo I, Gomez-Dominguez D, Sato M, Hayashi Y, Bayés À, Barco A, Lopez-Atalaya JP, de la Prida LM Cell Rep 2021 35(10):109229 https://doi.org/10.1016/j.celrep.2021.109229
Transcriptome and epigenome analysis of engram cells: Next-generation sequencing technologies in memory research Fuentes-Ramos M, Alaiz-Noya M, Barco A Neurosci Biobehav Rev 2021 127:865 https://doi.org/10.1016/j.neubiorev.2021.06.010
A Zic2-regulated switch in a noncanonical Wnt/betacatenin pathway is essential for the formation of bilateral circuits Morenilla-Palao C, López-Cascales MT, López-Atalaya JP, Baeza D, Calvo-Díaz L, Barco A, Herrera E Sci Adv 2020 6(46):eaaz8797 https://doi.org/10.1126/sciadv.aaz8797
KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain Lipinski M, Muñoz-Viana R, Del Blanco B, Marquez-Galera A, Medrano-Relinque J, Caramés JM, Szczepankiewicz AA, Fernandez-Albert J, Navarrón CM, Olivares R, Wilczyński GM, Canals S, Lopez-Atalaya JP, Barco A Nat Commun 2020 11(1):2588 https://doi.org/10.1038/s41467-020-16246-0
Transcriptome Analysis of iPSC-Derived Neurons from Rubinstein-Taybi Patients Reveals Deficits in Neuronal Differentiation Calzari L, Barcella M, Alari V, Braga D, Muñoz-Viana R, Barlassina C, Finelli P, Gervasini C, Barco A, Russo S, Larizza L Mol Neurobiol 2020 57(9):3685 https://doi.org/10.1007/s12035-020-01983-6
CBP and SRF co-regulate dendritic growth and synaptic maturation Del Blanco B, Guiretti D, Tomasoni R, Lopez-Cascales MT, Muñoz-Viana R, Lipinski M, Scandaglia M, Coca Y, Olivares R, Valor LM, Herrera E, Barco A Cell Death & Differentiation 2019 26(11):2208 https://doi.org/10.1038/s41418-019-0285-x
CBP/p300 in brain development and plasticity: disentangling the KAT’s cradle Lipinski M, Del Blanco B, Barco A Current Opinion in Neurobiology 2019 59:1 https://doi.org/10.1016/j.conb.2019.01.023
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models Hutson TH, Kathe C, Palmisano I, Bartholdi K, Hervera A, De Virgiliis F, McLachlan E, Zhou L, Kong G, Barraud Q, Danzi MC, Medrano-Fernandez A, Lopez-Atalaya JP, Boutillier AL, Sinha SH, Singh AK, Chaturbedy P, Moon LDF, Kundu TK, Bixby JL, Lemmon VP, Barco A, Courtine G, Di Giovanni S Sci Transl Med 2019 11(487):eaaw2064 https://doi.org/10.1126/scitranslmed.aaw2064
Contribution of spurious transcription to intellectual disability disorders Scandaglia M, Barco A Journal of Medical Genetics 2019 56(8):491 https://doi.org/10.1136/jmedgenet-2018-105668
Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus Fernandez-Albert J, Lipinski M, Lopez-Cascales MT, Rowley MJ, Martin-Gonzalez AM, Del Blanco B, Corces VG, Barco A Nature Neuroscience 2019 22(10):1718 https://doi.org/10.1038/s41593-019-0476-2
The Epigenetic Factor CBP Is Required for the Differentiation and Function of Medial Ganglionic Eminence-Derived Interneurons Medrano-Fernandez A, Delgado-Garcia JM, Del Blanco B, Llinares M, Sanchez-Campusano R, Olivares R, Gruart A, Barco A Molecular Neurobiology 2019 56(6):4440 https://doi.org/10.1007/s12035-018-1382-4
Early alteration of epigenetic-related transcription in Huntington’s disease mouse models Hervas-Corpion I, Guiretti D, Alcaraz-Iborra M, Olivares R, Campos-Caro A, Barco A, Valor LM Sci Rep 2018 8:9925 https://doi.org/10.1038/s41598-018-28185-4
Editorial on the Special Issue: Molecules and Cognition Barco A, Knafo S Neuroscience 2018 370:1 https://doi.org/10.1016/j.neuroscience.2017.11.003
Impact of environmental conditions and chemicals on the neuronal epigenome Del Blanco B, Barco A Curr Opin Chem Biol 2018 45:157 https://doi.org/10.1016/j.cbpa.2018.06.003
CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons Pardo L, Valor LM, Eraso-Pichot A, Barco A, Golbano A, Hardingham GE, Masgrau R, Galea E Sci Rep 2017 7:6390 https://doi.org/10.1038/s41598-017-06231-x
Epigenetic Etiology of Intellectual Disability Iwase S, Berube NG, Zhou Z, Kasri NN, Battaglioli E, Scandaglia M, Barco A J Neurosci 2017 37(45):10773 https://doi.org/10.1523/JNEUROSCI.1840-17.2017
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons Scandaglia M, Lopez-Atalaya JP, Medrano-Fernandez A, Lopez-Cascales MT, Del Blanco B, Lipinski M, Benito E, Olivares R, Iwase S, Shi Y, Barco A Cell Rep 2017 21(1):47 https://doi.org/10.1016/j.celrep.2017.09.014
Revitalizing genetically-modified mouse strains using frozen-thawed sperm after up to 192 h of refrigerated epididymis transportation Moreno-del Val G, Munoz-RobledanoP Lab Anim 2017 51(5):526 https://doi.org/10.1177/0023677217692612
Blocking miRNA Biogenesis in Adult Forebrain Neurons Enhances Seizure Susceptibility, Fear Memory, and Food Intake by Increasing Neuronal Responsiveness Fiorenza A, Lopez-Atalaya JP, Rovira V, Scandaglia M, Geijo-Barrientos E, Barco A Cereb Cortex 2016 26(4):1619 https://doi.org/10.1093/cercor/bhu332
Nuclear organization and 3D chromatin architecture in cognition and neuropsychiatric disorders Medrano-Fernandez A, Barco A Mol Brain 2016 9:83 https://doi.org/10.1186/s13041-016-0263-x
Role of Dicer and the miRNA system in neuronal plasticity and brain function Fiorenza A, Barco A Neurobiol Learn Mem 2016 135:3 https://doi.org/10.1016/j.nlm.2016.05.001
Specific promoter deacetylation of histone H3 is conserved across mouse models of Huntington’s disease in the absence of bulk changes Guiretti D, Sempere A, Lopez-Atalaya JP, Ferrer-Montiel A, Barco A, Valor LM Neurobiol Dis 2016 89:190 https://doi.org/10.1016/j.nbd.2016.02.004
Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury Pardo L, Schlüter A, Valor LM, Barco A, Giralt M, Golbano A, Hidalgo J, Jia P, Zhao Z, Jove M, Portero-Otin M, Ruiz M, Gimenez-Llort L, Masgrau R, Pujol A, Galea E Glia 2016 64(5):853 https://doi.org/10.1002/glia.22969
Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly Scandaglia M, Benito E, Morenilla-Palao C, Fiorenza F, del Blanco B, Coca Y, Herrera E, Barco A Sci Rep 2015 5:17470 https://doi.org/10.1038/srep17470
The Neuronal Activity-Driven Transcriptome Benito E, Barco A Mol Neurobiol 2015 51(3):1071 https://doi.org/10.1007/s12035-014-8772-z
Editorial Barco A, Brambilla R, Rosenblum K Neurobiol Learn Mem 2015 124:1 https://doi.org/10.1016/j.nlm.2015.08.001
cAMP Responsive Element Binding Protein (CREB) and cAMP Co-regulate Activator Protein 1 (AP1)-Dependent Regeneration-Associated Gene Expression and Neurite Growth Ma TC, Barco A, Ratan RR, Willis DE J Biol Chem 2014 289(47):32914 https://doi.org/10.1074/jbc.M114.582460
Can changes in histone acetylation contribute to memory formation? Lopez-Atalaya J, Barco A Trends Genet 2014 30(12):529 https://doi.org/10.1016/j.tig.2014.09.003
Epigenetic factors in intellectual disability: the Rubinstein-Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin Lopez-Atalaya JP, Valor LM, Barco A Prog Molec Biol Transl Sci 2014 128:139 https://doi.org/10.1016/B978-0-12-800977-2.00006-1
Histone Acetylation and CREB Binding Protein Are Required for Neuronal Resistance against Ischemic Injury Yildririm F, Ji SB, Kronenberg G, Barco A, Olivares R, Benito E, Dirnangl U, Gertz K, Endres M, Harms C, Meisel A PLoS One 2014 9(4):e95465 https://doi.org/10.1371/journal.pone.0095465
Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction Ito S, Magalska A, Alcaraz-Iborra M, Lopez-Atalaya JP, Rovira V,Contreras-Moreira B, Lipinski M, Olivares R, Martinez-Hernandez J,Ruszczycki B, Lujan R,Geijo-Barrientos E,Wilczynski GM, Barco A Nat Commun 2014 5:4450 https://doi.org/10.1038/ncomms5450
Neuroepigenetic disorders: Progress, promises and challenges. Barco A Neuropharmacology 2014 80:1 https://doi.org/10.1016/j.neuropharm.2014.02.013
Genomic landscape of transcriptional and epigenetic dysregulation in early-onset polyglutamine disease Valor LM, Guiretti D, Lopez-Atalaya JP, Barco A J Neurosci 2013 33(25):10471 https://doi.org/10.1523/JNEUROSCI.0670-13.2013
Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibiton Lopez-Atalaya JP, Ito S, Valor LM, Benito E, Barco A Nucleic Acids Res 2013 41(17):8072 https://doi.org/10.1093/nar/gkt590
Histone H3 lysine methylation in cognition and intellectual disability disorders Parkel S, Lopez-Atalaya JP, Barco A Learn Mem 2013 20(10):570 https://doi.org/10.1101/lm.029363.112
Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders Valor LM, Viosca J, Lopez-Atalaya JP, Barco A Curr Pharm Design 2013 19(28):5051
Enhanced cAMP Response Element-Binding Protein Activity Increases Neuronal Excitability, Hippocampal Long-Term Potentiation, and Classical Eyeblink Conditioning in Alert Behaving Mice Gruart A, Benito E, Delgado-Garcia JM, Barco A J Neurosci 2012 32(48):17431 https://doi.org/10.1523/JNEUROSCI.4339-12.2012
Hippocampal gene profiling: Toward a systems biology of the hippocampus Valor LM, Barco A Hippocampus 2012 22(5):929 https://doi.org/10.1002/hipo.20888
Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome Lopez-Atalaya JP, Gervasini C, Mottadelli F, Spena S, Piccione M, Scarano G, Selicorni A, Barco A, Larizza L J Med Genet 2012 49(1):66 https://doi.org/10.1136/jmedgenet-2011-100354
Ablation of CBP in Forebrain Principal Neurons Causes Modest Memory and Transcriptional Defects and a Dramatic Reduction of Histone Acetylation But Does Not Affect Cell Viability Valor LM, Pulopulos MM, Jimenez-Minchan M, Olivares R, Lutz B, Barco A J Neurosci 2011 31(5):1652 https://doi.org/10.1523/JNEUROSCI.4737-10.2011
cAMP Response Element-Binding Protein Is a Primary Hub of Activity-Driven Neuronal Gene Expression Benito E, Valor JM, Jimenez-Minchan M, Huber W, Barco A J Neurosci 2011 31(50):18237 https://doi.org/10.1523/JNEUROSCI.4554-11.2011
CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement Lopez-Atalaya JP, Ciccarelli A, Viosca J, Valor LM, Jimenez-Minchan M, Canals S, Giustetto M, Barco A EMBO J 2011 30(20):4287 https://doi.org/10.1038/emboj.2011.299
Genetic Approaches to Investigate the Role of CREB in Neuronal Plasticity and Memory Barco A, Marie H Mol Neurobiol 2011 44(3):330 https://doi.org/10.1007/s12035-011-8209-x
CREB’s control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models Benito E, Barco A Trends Neurosci 2010 33(5):230 https://doi.org/10.1016/j.tins.2010.02.001
Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology Viosca J, Lopez-Atalaya JP, Olivares R, Eckner R, Barco A Neurobiol Dis 2010 37(1):186 https://doi.org/10.1016/j.nbd.2009.10.001
Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function Valor LM, Jancic D, Lujan R, Barco A Cell Death Differ 2010 17(10):1636 https://doi.org/10.1038/cdd.2010.40

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CBP is required for establishing adaptive gene programs in the adult mouse brain.

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Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding

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Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly.

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