Scientist of the month: Esteban Ballestar

Esteban Ballestar tells us about work in his lab focusing on active DNA methylation, and new developments in the field.

Brief biography

Esteban Ballestar PhD

Esteban Ballestar obtained his PhD from the University of Valencia under the supervision of Luis Franco, specializing in chromatin and histone modifications. He then joined the group of Alan Wolffe at the National Institutes of Health (NIH) as a postdoctoral fellow, where he investigated associations between nuclear factors such as methyl-CpG binding proteins and methylated DNA. From 2001 to 2008, Esteban Ballestar worked as a senior scientist at the Spanish National Cancer Research Center (CNIO), in association with Manel Esteller, working on epigenetic alterations in human cancer.

Esteban is currently a senior group leader at the Bellvitge Institute for Biomedical Research (PEBC-IDIBELL) in Barcelona working on epigenetic deregulation in the context of autoimmune diseases, focusing on DNA methylation changes and various differentiation models relevant to this group of disorders. He has authored more than 90 publications. Esteban is recipient of various national and international grants and has organized several international conferences on epigenetics.

Q. What sparked your passion for science?

Since my early childhood, I have always been attracted to nature, and as I grew up my interest shifted more towards nature at a smaller scale, trying to understand how cells work. Getting my first microscope as a kid probably pushed further my interest on cells.

At a more social level, I strongly believe in the idea that research is a way to give useful contributions to human kind and this is one of my motivations.

Q. What discoveries and next steps does your lab have in store for us?

One of the questions that I am most interested in is which mechanisms are behind active DNA demethylation? How is it targeted? Which elements, transcription factors or signaling pathways participate in this process? Are some of the intermediate nucleosides in the demethylation pathway bona fide epigenetics marks? The directionality of changes in DNA methylation and their functional significance in various processes is also interesting to us.

In my lab, we are focusing on terminal differentiation processes in the myeloid branch of hematopoiesis. Some of these processes are relevant in the context of autoimmune diseases and in cancer. These differentiation models are ideal to investigate active DNA methylation and its functional relevance, as well as how external signals and cell signaling pathways drive and target DNA methylation changes.

Identification of specific pathways can be relevant for understanding how DNA methylation or demethylation is targeted and this information can also be important to modulate these changes in exacerbated differentiation in the context of disease.

Q. What made you focus on epigenetics research?

During my early research years, the notion of an epigenetic code was starting to become apparent and questions such as the specificity of histone modifications and their functional and structural consequences were very appealing to me.

Q. You present a webinar on DNA methylation changes during cell differentiation. What new and exciting developments can we hear more of during the webinar?

Our knowledge of active demethylation mechanisms has increased abruptly in the past few years. We now have a deeper knowledge of the role of eukaryotic CpG methylation, both spatially and temporally. In my webinar, I will present and discuss the many roles of DNA methylation and its relevance to various aspects of genome biology, with particular focus on differentiation processes. I will also provide novel data on targeting of DNA methylation processes and discuss DNA demethylation mechanisms and how it is targeted. 

I hope to challenge the prevailing view of DNA methylation as a sort of static epigenetic mark and open the discussion to the more dynamic role of DNA methylation changes in biological processes.

Q. Where do you see things going? What do you think will be the next big breakthrough in epigenetics research?

I see several aspects that will fully develop in the next few years. The integration and translation of individual and combined maps of different epigenetic marks at the genomic level into functional consequences for gene regulation and nuclear architecture, for a wide range of cell types, will lead us to a deep knowledge on the layers of regulation. This will have important implications for development, cell cycle and their deregulation in human disease. Also, we will soon have abundant data on the functional epigenome at the single cell level.

Hopefully, in the next few years we will have a better view of the real contributions of epigenetic alterations in a wide range of human diseases, and the possibility of generating specific epigenetic drugs will also constitute a major breakthrough.

Q. What are the highlights of your career so far?

During my postdoc at NIH and during my subsequent period at the CNIO, we completed several seminal studies reinforcing the notion of the strong links between DNA methylation, histone modifications and transcriptional control, both in normal cells and in cancer.

Additionally, at the PEBC-IDIBELL my team has published some of the first articles highlighting the relevance of DNA methylation changes in the context of autoimmune disease in monozygotic twins discordant for these diseases. 

I also have a long term interest in DNA demethylation, and we have published several papers on the interplay between transcription factors and DNA demethylation. In the coming months, my team will make novel significant contributions in the targeting of DNA demethylation processes in differentiation.

Q. Any words of wisdom for young researchers just starting?

Two major pieces of advice for fresh researchers: one, make good choices in terms of relevant scientific questions and picking the right laboratory to address them (the latter, for students and early postdocs); this involves deep 'pre-research' and discussions. Second, stick to your choices (at least for some time!), be relentless and find solutions to the many obstacles (technical or otherwise) that will surely come up.

Q. What would you be working on if you weren't an epigeneticist?

In biology, I would be working in neuroscience. Outside biology, mathematics is one of my long-term interests. Outside science, music is my passion.

Q. One thing you could not live without (inside or outside the lab)?

Family, friends and music.


  • De la Rica L, Rodríguez-Ubreva J, García M, Islam A, Urquiza JM, Hernando H, Christensen J, Helin K, Gómez-Vaquero C, Ballestar E (2013). PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation. Genome Biology, 14, R99.
  • Hernando H, Shannon-Lowe C, Islam A, Al-Shahrour F, Rodríguez-Ubreva J, Rodríguez-Cortez VC, Javierre BM, Mangas C, Fernandez AF, Parra M, Delecluse H-J, Esteller M, Lopez-Granados E, Fraga MF, Lopez-Bigas N, Ballestar E (2013). The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion. Genome Biology, 14, R3.
  • Kallin EM, Rodríguez-Ubreva J, Christensen J, Cimmino L, Aifantis I, Helin K, Ballestar E, Graf T (2012). Tet2 facilitates the derepression of myeloid target genes during cebpα-induced transdifferentiation of pre-B cells. Molecular Cell, 48, 266–276.
  • Rodriguez-Ubreva J, Ciudad L, Gómez-Cabrero D, Parra M, Bussmann LH, di Tullio A, Kallin EM, Tegnér J, Graf T, Ballestar E (2012). Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes. Nucleic Acids Research, 40, 1954–1968.
  • Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreño L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E (2010). Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Research, 20, 170–179.

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