Historical
 
Grupo de Cromatina y Enfermedad  
Dr. Esteban Ballestar

Grupo de Cromatina y Enfermedad
Group Leader: Dr. Esteban Ballestar



 
  RESEARCH TEAMS  
 

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Dr Manel Esteller

Grupo de Epigenética del Cáncer
 

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Dra. Montse Sanchez-Cespedes

Grupo de Genes y Cáncer
 

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Dr .Alejandro Vaquero

Grupo de Biología de la Cromatina
 

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Dr. Esteban Ballestar

Grupo de Cromatina y Enfermedad
 

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Dra. Ethel Queralt

Grupo de Ciclo Celular
 

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Dr. Dave Monk

Grupo de Impronta Genómica y Cáncer
 

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Dra. Maribel Parra

Grupo de Diferenciación Celular
 

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Dra. Purificación Muñoz

Grupo de Envejecimiento y Cáncer
 

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Dra. Eva Gonzalez-Suarez

Grupo de Transformación y Metástasis
 

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PEBC

Apoyo Genómico
 

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PEBC

Apoyo bioinformático
 

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PEBC

Apoyo Administrativo a la Investigación
 

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PEBC

Servicio de Apoyo
 
 
     
  Group description


The Chromatin and Epigenetics fields have experienced a spectacular development in the last few years. Key breakthroughs include the identification of a code of histone modifications associated with specific functions, the finding of mechanistic links between DNA methylation and histone modifications or the recognition that epigenetic modifications and chromatin organization not only define cell identity but also constitutes a dynamic readout of environment. But most importantly, the identification of alterations in chromatin structure and epigenetic regulation in diseases including cancer, autoimmune disease, and a variety of syndromes, have added a clinical dimension to studies in chromatin and epigenetics, since these alterations are potentially reversible.

The study of lymphocyte differentiation and activation allows us to understand not only mechanisms of epigenetic regulation and chromatin organization but also how the abnormal control of these pathways can lead to abnormal behaviour in haematopoietic malignancies or other diseases such as autoimmune disorders. Appropriate cell fate decissions and maintenance of homeostasis are key in maintaining the normal behaviour of haematopoietic and immune system. Lymphocyte differentiation and activation involve many different transcription factors, including Runx1, PAX5, GATA3, all Ikaros and Notch family members or polycomb group proteins, that associate with the epigenetic machinery. In general, subsequent and specific expression of these transcription factors is associated with differentiation. Additionally, microRNAs (miRNAs), an important group of transcriptional regulators that affect the translation and/or the stability of protein-coding transcripts, have also been involved in lymphocyte differentiation. These processes are orchestrated in response to discrete intracellular signaling pathways, including phosphorylation cascades that culminate in the activation of mitogen-activated protein kinases (MAPKs). Connections between signaling cascades and epigenetic modifications have particular relevance for cells that participate in immune and inflammatory response.

In this context, there are fundamental questions that remain to be aswered including the mechanisms of epigenetic regulation of transcription factors and miRNAs and their functional consequences in lymphocyte differentation. In addition, the mechanisms by which signaling pathways result in epigenetic regulation are unknown. The consequences of misregulation of these processes have been proposed to participate in haematopoietic disorders, including leukemias, lymphomas on one hand, or autoimmune disease, on the other; however the detailed mechanisms are also unknown. Our group is focused on the epigenetic alterations the haematopoietic system and their connections with upstream signaling pathways.


Research Lines:

-Chromatin Deregulation Processes involved in Haematopoietic Malignancies. Different families of transcriptional regulators, such as the Ikaros, the Notch or Polycomb families of proteins have been demonstrated to be involved in different stages of lymphocyte differentiation. Some of these factors are expressed in a multiplicity of isoforms with specific activities. These factors control the switching on and off of many genes through the epigenetic modification of their regulatory sequences in their chromatin context. The misregulation of some of these factors has been proposed to play a role in malignant transformation. In particular, epigenetic inactivation of these factors has been proposed to play a role in dedifferentiation. However, the mechanisms need to be solved. Aberrant hypermethylation of the promoter CpG islands surely participates in the epigenetic inactivation of some of these factors. In these processes, factors that translate the DNA methylation signal into a silenced transcriptional state, such as MBD proteins, not only contribute to the epigenetic pathway to malignant transformation, but are also potential targets for therapy.

We are currently interested in investigating the implication of the epigenetic inactivation of transcriptional factors involved in lymphocyte differentiation in the development of haematopoietic malignancies. For instance, when analysing at all the Ikaros family members we have found that some are specifically methylated in certain lymphomas and leukemias. Methylation of Ikaros and Aiolos may contribute to an impairment of differentiation.

Recently, miRNAs have also been implicated in many differentiation processes. In fact, there are specific sets of miRNAs expressed per cell in different stages of lymphocyte differentiation. We are also interested in investigating the epigenetic mechanisms that control miRNA expression throughout lymphocyte differentiation and their functional consequences.

-Epigenetic Mechanisms involved in T cell Activation processes. Exposure of naive lymphocytes to antigens results in further differentiation, in a process known as activation. Proinflammatory cytokines and microbial products stimulate transcription of several genes involved in the inflammatory and immune response through the coordinate induction of multiple signaling pathways, including three major mitogen-activated protein kinase (MAPK) pathways –Erks, p38 and c-Jun kinases. One of the most studied MAPKs, p38, has been directly involved in the expression of several immune response genes through chromatin signaling. T cells activate p38 MAPK via two distinct pathways, the classical MAPK cascade and a newly described alternative pathway, which is independent of MAPKK-mediated phosphorylation. Recently, Gadd45a has been found to inhibit this T cell specific p38 activity, however the downstream events are still unclear. Interestingly, T cell activation has been demonstrated to be associated with selective demethylation of the regulatory sequences of key genes, such as interleukins, interferon etc. On the other hand, in a different context, gadd45a has been recently reported to promote active demethylation.
In order to investigate the connections between the p38 MAPK pathway and the epigenetic regulation of proinflammatory genes, we are studying the epigenetic consequences of genetic or pharmacological inhibition of p38, and subsequent blockage of lymphocyte activation, in the promoter of inflammatory genes in T cells.

-Epigenetic Deregulation in Autoimmune Disease. Epigenetic alterations have long been recognized to occur in autoimmune disease. At a macroscopic level, the epigenetic contribution to the development of autoimmunity is also evidenced in monozygotic twins that are discordant for the disease. An archetypical example of autoimmune disease is provided by systemic lupus erythematosus (SLE), a disease in which both increased rate of apoptosis of T cells, with subsequent release of nuclear components, and exacerbated activation of T and B-cells occur. In both processes, epigenetic alterations have been proposed to be implicated. Remarkably, both global and gene-specific promoter demethylation occur in T cells isolated from both a SLE mouse model and SLE patients. In addition, several histone deacetylase (HDAC) and DNA methyltransferase inhibitors affect the epigenetic status of inflammatory genes in T cells isolated from SLE patients and have effects in the phenotype of both SLE patients and murine models. Interestingly, Gadd45a knockout mice, which show hyperactivation of T cells, develop a SLE-like phenotype.
One of the aims of our group will focus on the study of the epigenetic mechanisms implicated in autoimmune disease, as a strategy to better understand epigenetic regulation of lymphocyte activation. Our research plan is focused in obtaining detailed maps of epigenetic alterations in T and B cells from both mouse models for SLE and human samples. This characterization will be followed by a characterization of the elements of the chromatin machinery involved in the establishment of the proper and aberrant proifile of epigenetic marks and a study of potential reversion of altered patterns. Finally, a study of the implication of upstream signalling cascades (p38 MAP and PI3K) in the generation of aberrant chromatin patterns will be studied.





  Leader Bio
 
Esteban Ballestar (Valencia, España, 1969) licenciado en Biología por la Universitat de Valencia, donde también obtuvo el doctorado en el año 1997 bajo la dirección del profesor Luis Franco, está especializado en modificaciones de la cromatina y de las histonas. En su tesis doctoral, el Dr. Ballestar identificó y caracterizó una nueva modificación de las histonas. De 1997 a 2000, el Dr. Ballestar realizó una estancia postdoctoral en el laboratorio del Dr. Alan Wolffe en los National Institutes of Health, (Bethesda, MD, EEUU) donde investigó la asociación entre elementos de la maquinaria modificadora de las histonas y el DNA metilado.

Allí, el Dr. Ballestar contribuyó a demostrar que las proteínas con el dominio de unión a DNA metilado (MBD) interaccionan con elementos de la maquinaria de remodelación de la cromatina y enzimas modificadoras de las histonas para silenciar los genes. Además, su trabajo con las proteínas MBDs demostró la capacidad de éstas para asociarse con genes específicos y su implicación en desregulación epigenética en el síndrome de Rett. De 2001 a 2008, Esteban Ballestar trabajó en el Laboratorio de Epigenética del Centro Nacional de Investigaciones Oncológicas (CNIO) en asociación con el Dr. Manel Esteller, donde su principal campo de investigación ha sido el estudio de la implicación de los factores de la cromatina en las alteraciones epigenéticas en el cáncer humano. En este periodo, contribuyó a demostrar el papel de las MBDs en la desregulación epigenética en cáncer y en el síndrome de Rett. También en su etapa en el CNIO, contribuyó en artículos sobre las alteraciones en el perfil de la modificación de las histonas asociadas con hipometilación en cáncer y la acumulación de cambios epigenéticos vinculados a la edad.  Desde 2002, Ballestar ha coordinado con el Dr. Esteller un curso de doctorado en Epigenética del Cáncer de la Universidad Autónoma de Madrid. Desde 2004, el Dr. Ballestar ha conseguido financiación para varios proyectos destinados a desarrollar una línea independiente de investigación en epigenética y alteraciones de la cromatina en el contexto de procesos autoinmunes.

Como Jefe del Grupo de Cromatina y Enfermedad del Programa de Epigenética y Biología del Cáncer del Instituto de Biomedicina de Bellvitge (IDIBELL) de Barcelona, dedica su investigación al estudio de los mecanismos de desregulación epigenética en el contexto del sistema hematopoyético en enfermedades autoinmunes y cánceres hematológicos.

Es el autor de más de cincuenta artículos acreditados en ciencias biomédicas. Es también miembro de diversas sociedades científicas y revisor en múltiples revistas y agencias nacionales e internacionales.


       
  Selected publications

 

 flecha Ballestar E. (2011) Epigenetics Alterations in Autoimmune Rheumatic Diseases. Nature Reviews Rheumatology 7, 263-271.

 flecha Rodriguez-Ubreva, J., Ciudad, L., Gómez-Cabrero, D., Parra, M., Bussmann, L.H., di Tullio, A., Kallin, E.M., Tegnér, J., Graf, T. and Ballestar, E. (2011) Pre-B Cell to Macrophage Transdifferentiation Without Significant Promoter DNA Methylation Changes. Nucleic Acids Research. doi: 10.1093/nar/gkr1015.

 flecha Rodriguez-Cortez, V.C., Hernando, H., de la Rica, L., Vento, R., and Ballestar, E. (2011) Epigenomic Deregulation in the Immune System. Epigenomics 3, 697-713.

 flecha Javierre, B.M., Rodriguez-Ubreva, J., Al-Shahrour, F., Corominas, M., Graña, O., Ciudad, L., Agirre, X. Pisano, D.G, Valencia, A., Roman-Gomez, J., Calasanz, M.J., Prosper, F., Esteller, M., Gonzalez-Sarmiento, R., Ballestar, E. (2011) Long-Range Epigenetic Silencing Associates with Deregulation of Ikaros Targets in Colorectal Cancer Cells. Molecular Cancer Research. 9, 1139-1151.

 flecha Javierre, B.M., Fernandez, A.F., Richter, J., Al-Shahrour, F., Martin-Subero, J.I., Rodriguez-Ubreva, J., Berdasco, M., Fraga, M.F., O'Hanlon, T.P., Rider, L.G., Jacinto, F.V., Lopez-Longo, F.J., Dopazo, J., Forn, M., Peinado, M.A., Carreño, L., Sawalha, A.H., Harley, J.B., Siebert, R., Esteller, M., Miller, F.W., and Ballestar, E. (2010) Changes in the Pattern of DNA Methylation Associate with Twin Discordance in Systemic Lupus Erythematosus. Genome Res. 20, 170-179.

 flecha Bussman, L., Schubert, A., Vu Manh, T.P., DE Andres, L., Desbordes, S., Parra, M., Zimmermann, T., Rapino, F., Rodriguez-Ubreva, J., Ballestar, E., Graf, T. (2009) A robust and highly efficient immune cell reprogramming system. Cell Stem Cell 5, 554-566.

 flecha Javierre, B.M., Esteller, M. and Ballestar, E. (2008) Epigenetic Connections between Autoimmune Disorders and Haematological Malignancies. Trends in Immunology 29, 616-623.

 flecha Ballestar, E. and Esteller, M. (2008) Snapshot: The Human DNA Methylome in Health and Disease. Cell 135, 1144 - 1144.e1.

 flecha Caballero R, Setien F, Lopez-Serra L, Boix-Chornet M, Fraga MF, Ropero S, Megias D, Alaminos M, Sanchez-Tapia EM, Montoya MC, Esteller M, Gonzalez-Sarmiento R, Ballestar E. Combinatorial effects of splice variants modulate function of Aiolos. J Cell Sci. 2007 Aug 1;120(Pt 15):2619-30.

 flecha Grego-Bessa J, Luna-Zurita L, del Monte G, Bolós V, Melgar P, Arandilla A, Garratt AN, Zang H, Mukouyama YS, Chen H, Shou W, Ballestar E, Esteller M, Rojas A, Pérez-Pomares JM, de la Pompa JL.Notch signaling is essential for ventricular chamber development. Dev Cell. 2007 Mar;12(3):415-29.

 flecha Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, Ballestar E, Sousa-Victor P, Baeza-Raja B, Jardí­ M, Bosch-Comas A, Esteller M, Caelles C, Serrano AL, Wagner EF, Muñoz-Cánoves P.Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. EMBO J. 2007 Mar 7;26(5):1245-56.

 flecha Boix-Chornet M, Fraga MF, Villar-Garea A, Caballero R, Espada J, Nunez A, Casado J, Largo C, Casal JI, Cigudosa JC, Franco L, Esteller M, Ballestar E. Release of hypoacetylated and trimethylated histone H4 is an epigenetic marker of early apoptosis. J Biol Chem. 2006 May 12;281(19):13540-7.

 flecha Ballestar E, Esteller M, Richardson BC. The epigenetic face of systemic lupus erythematosus. J Immunol. 2006 Jun 15;176(12):7143-7.

 flecha Ballestar E, Esteller M. Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger. Biochem Cell Biol. 2005 Jun;83(3):374-84.

 flecha Ballestar E, Esteller M. The epigenetic breakdown of cancer cells: from DNA methylation to histone modifications. Prog Mol Subcell Biol. 2005;38:169-81.

 flecha Ballestar E, et al.The impact of MECP2 mutations in the expression patterns of Rett syndrome patients. Hum Genet. 2005 Jan;116(1-2):91-104.

 flecha Ballestar E, et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 2003 Dec 1;22(23):6335-45.

 flecha Ballestar E, Wolffe AP.Methyl-CpG-binding proteins. Targeting specific gene repression.Eur J Biochem. 2001 Jan;268(1):1-6.

 flecha Ballestar E, Yusufzai TM, Wolffe AP.Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA.Biochemistry. 2000 Jun 20;39(24):7100-6.

 flecha Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP.Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation.Nat Genet. 1999 Sep;23(1):62-6.


 

  Members
NAME E-MAIL URL

Dr. Esteban Ballestar

 Jefe de Grupo

eballestar@idibell.cat

Dr. Fco. Javier Rodriguez-Ubreva

 Investigador Postdoctoral

jrubreva@idibell.cat

Lorenzo de la Rica

 Estudiante de Doctorado

ldelarica@idibell.cat

Roser Vento

 Estudiante de Doctorado

rvento@idibell.cat

Virginia Rodriguez

 Estudiante de Doctorado

vcrodriguez@idibell.cat

Laura Ciudad

 Tecnico Superior

lciudad@idibell.cat

 
 

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