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Lab presentation

During neurogenesis a delicate balance between stability and plasticity is essential; in one sense, stability to allow the pool of neural progenitor cells to proliferate and propagate the cell identity to daughter cells; and plasticity to provide a window to modify this identity and allow differentiation. This balance is preserved by the coordinated action of epigenetic regulators and transcription factors that respond to developmental signals.

Our group is focused on understanding the role of epigenetics in gene transcription during neurogenesis. The final goal is to define the principles that control the activity of our genome to establish and maintain the cell identity during early neurogenesis. We study mechanisms of gene expression at different levels, from the action of epigenetic regulators, their interplay with developmental signals, to how the genomic loci are positioned in the 3D space within cell nuclei.

Moreover, epigenetic alterations are common in a wide spectrum of diseases, from developmental disorders to many types of cancers. With our studies we expect to pave the way towards deeper understanding on how deregulation of these epigenetic factors leads to disease focusing in intellectual disability, helping to develop therapeutic and diagnostic tools.

Lab_presentation_Marian Martinez_2

Projects

EPIGENETIC DEFECTS IN MENTAL RETARDATION

A very high number of genes mutated in mental retardation encode regulators of chromatin structure. One of these genes is PHF8, a histone demethylase enzyme. The PHF8 function and the molecular mechanisms responsible for its role in mental retardation are not clearly established. In the laboratory we are interested in unraveling the role of PHF8 in vivo.

Projects_MarianMartinez_1

THE ROLE OF HISTONE METHYLATION DURING NEUROGENESIS

Neural differentiation requires general changes in gene expression in which epigenetic factors are involved. Our work has identified several signalling pathways that cooperate with the enzymes responsible of H3K27me3 to control neurogenesis. Our goal is to describe the molecular mechanisms responsible of this cooperation using the chicken neural tube and neural stem cells as models.

Projects_MarianMartinez_2

GENOME ARCHITECTURE AND CELL IDENTITY

Long-range gene regulation works through chromatin looping mechanisms that bring together the promoters of genes with distant regulatory regions. In addition, enhancers also co-associate with other enhancers in 3D space that change during development and that will facilitate their activation. We are studying how epigenetic regulators (JMJD3 and PHF2) integrate with developmental signals to modify the genome architecture, in particular the formation of enhancer-clusters and the lamina anchorage.

Projects_MarianMartinez_3

Our strategy for unraveling the principles of genome function in development aims to integrate cellular and molecular biology, epigenetics, nuclear imaging and proteomics technologies.

Projects_MarianMartinez_4

Lab people

Principal investigator

Graduated in pharmacology from the Santiago de Compostela University. Marian
Martínez-Balbás obtained her PhD at the Polytechnic University of Barcelona studying
DNA and chromatin structure. She was a postdoctoral Fellow at the NIH (USA) where
she focused on chromatin remodeling and dynamics at Dr C Wu’s laboratory. She then
moved to Cambridge (UK) to the J Gurdon Institute (to the group of Dr T Kouzarides) to
study the contribution of epigenetics mechanisms to cell cycle progression, cell
proliferation and development.

In 2000 she got a permanent CSIC position at the IBMB to start a new group. Her research investigation is focused on understanding the role of several chromatin regulators controlling the transcriptional program during development in a cell-type specific manner.

Her group analyzes different aspects of chromatin dynamics during neurogenesis using in vitro (neural stem cells) and in vivo models (chicken neural tube) in physiological and pathological conditions, focusing in the role of epigenetics in intellectual disability.

Past students

Selected publications

Iacobucci S, Padilla N, Gabrielli M, Navarro C., Lombardi M, Vicioso-Mantis M, Verderio C, de la Cruz X, Martínez-Balbás MA. (2021) The histone demethylase PHF8 regulates astrocyte differentiation and function. Development, 148, dev194951.

https://journals.biologists.com/dev/article-abstract/148/12/dev194951/269266/


Pappa S, Padilla N, Iacobucci S, Vicioso M, Álvarez de la Campa E, Navarro C, Marcos E, de la Cruz X, Martínez-Balbás MA. (2019) PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors. Proc Natl Acad Sci U S A;116, 19464-19473.

https://doi.org/10.1073/pnas.1903188116


Fueyo R, Iacobucci S, Pappa S, Estarás C, Lois S, Vicioso-Mantis M, Navarro C, Cruz-Molina S, Reyes JC, Rada-Iglesias Á, de la Cruz X, Martínez-Balbás M.A. (2018) Lineage specific transcriptio factors and epigenetic regulators mediate TGFb-dependent enhancer activation. Nucleic Acids Research. 46,3351-3365.

https://www.ncbi.nlm.nih.gov/pubmed/29438503


Le Dréau G, Escalona R, Fueyo R, Herrera A, Martínez JD, Usieto S, Menendez A, Pons S, Martinez-Balbas MA, Marti. 2018 E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors activity in an E-box-dependent manner. Elife. pii: e37267.

https://elifesciences.org/articles/37267


Asensio-Juan E, Fueyo R, Pappa E, Iacobucci S, Badosa C, Lois  S, Balada M, Bosch-Presegué L, Vaquero A,  Gutiérrez S, Caelles C, Gallego C, de la Cruz X, and Martínez-Balbás MA. (2017) The histone demethylase PHF8 is a molecular safeguard  of the IFNγ response. Nucleic Acids Research, 45, 3800-3811.

https://doi.org/10.1093/nar/gkw1346


Akizu N,  García MA, Estarás C, Fueyo R, de la Cruz, X, and Martínez-Balbás MA. (2016). EZH2 regulates neuroepithelium structure and neuroblast proliferation by  repressing p21. Open Biology, 4, 150227.

http://rsob.royalsocietypublishing.org/content/royopenbio/6/4/150227.full.pdf


Sánchez-Molina S, Estarás C, Oliva JL, Akizu N, Asensio-Juan E, Rojas JM, and Martínez-Balbás MA. (2014) Regulation of CBP and Tip60 coordinates histone acetylation at local and global level during Ras induced transformation. Carcinogenesis, 35: 2194-2202.

https://academic.oup.com/carcin/article/35/10/2194/322625


Estarás C, Fueyo R, Akizu N,  Beltrán S, and Martínez-Balbás MA. (2013) RNA polymerase progression through H3K27me3-enriched gene bodies require JMJD3 histone demethylase. Molecular Biology Cell, 24: 351-360. Highligted in MBC.

https://www.molbiolcell.org/doi/pdf/10.1091/mbc.E12-07-0561


Asensio-Juan E, Gallego C, and Martínez-Balbás MA. (2012) Histone demethylase PHF8 is essential for cytoskeleton dynamics. Nucleic Acids Research, 40, 9429-9440.

https://academic.oup.com/nar/article/40/19/9429/2414741


Estarás C, Akizu N,  García MA, de la Cruz, X, and Martínez-Balbás MA. (2012) Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development, 139, 2681-2691.

https://journals.biologists.com/dev/article/139/15/2681/45112/

All publications

 

Iacobucci S, Padilla N, Gabrielli M, Navarro C., Lombardi M, Vicioso-Mantis M, Verderio C, de la Cruz X, Martínez-Balbás MA. The histone demethylase PHF8 regulates astrocyte differentiation and function. (2021) Development, 148, dev194951.


Pappa S, Padilla N, Iacobucci S, Vicioso M, Álvarez de la Campa E, Navarro C, Marcos E, de la Cruz X, Martínez-Balbás MA.  PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors.  (2019) Proc Natl Acad Sci U S A, 116, 19464-19473.


Le Dréau G, Escalona R, Fueyo R, Herrera A, Martínez JD, Usieto S, Menendez A, Pons S, Martinez-Balbas MA, Marti. E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors activity in an E-box-dependent manner. (2018) Elife, pii: e37267.


Fueyo R, Iacobucci S, Pappa S, Estarás C, Lois S, Vicioso-Mantis M, Navarro C, Cruz-Molina S, Reyes JC, Rada-Iglesias Á, de la Cruz X, Martínez-Balbás M.A. Lineage specific transcription factors and epigenetic regulators mediate TGFb-dependent enhancer activation. (2018) Nucleic Acids Research, 46, 3351-3365.


Asensio-Juan E, Fueyo R, Pappa S, Iacobucci S, Badosa C, Lois  S, Balada M, Bosch-Presegué L, Vaquero A,  Gutiérrez S, Caelles C, Gallego C, de la Cruz X,  Martínez-Balbás MA. The histone demethylase PHF8 is a molecular safeguard of the IFNγ response (2017) Nucleic Acids Research, 45, 3800-3811.


Sánchez-Cid L, Pons M, Lozano JJ, Rubio N, Guerra-Rebollo M, Soriano A, Paris-Coderch L, Segura MF, Fueyo R, Arguimbau J, Zodda E, Bermudo R, Alonso I, Caparrós X, Cascante M, Rafii A, Kang Y, Martínez-Balbás MA, Weiss SJ, Blanco J, Muñoz M, Fernández PL, Thomson TM. MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells. (2017) Oncotarget, 8, 83384-83406.


García MA, Fueyo R, Martínez-Balbás MA. Lysine demethylases: structure, function and disfunction (2016) Título del libro: “Chromatin signaling”. Editorial: Elsevier. Editores: O. Binda y M.E. Fernández-Zapico. eBook ISBN: 9780128026090. Hardcover. ISBN: 9780128023891.


Akizu N,  García MA, Estarás C, Fueyo R, de la Cruz X, Martínez-Balbás MA.  EZH2 regulates neuroepithelium structure and neuroblast proliferation by repressing p21. (2016) Open Biology, 4, 150227.


Akizu N, Martínez-Balbás MA. EZH2 orchestrates apicobasal polarity and neuroepithelial cell renewal. Comment (2016) Neurogenesis, Published Online: 17 Nov 2016.


Fueyo R,*, García MA,* Martínez-Balbás MA. Jumonji family histone demethylases in neural development (Requested Review) (2015) Cell and Tissue Research, 359, 87-98. * Equally contributing authors


Petazzi P,* Akizu N,*  García MA, Estarás C, Martínez de Paz A,  Rodriguez-Paredes M, Martínez-Balbás MA, Huertas D, Esteller M. Fine-tuning of MeCP2 expression is essential for proper nervous system development. (2014) Neurobiology of Disease, 67:49-56. * Equally contributing authors


Sánchez-Molina S, Estarás C, Oliva JL, Akizu N, Asensio-Juan E, Rojas JM,  Martínez-Balbás MA. Regulation of CBP and Tip60 coordinates histone acetylation at local and global level during Ras induced transformation. (2014) Carcinogenesis, 35, 2194-202.


Vidal-Laliena M, Gallastegui E, Mateo F, Martínez-Balbás MA, Pujol MJ, Bachs O. HDAC3 regulates cyclin A stability. (2013) J.  Biol. Chem, 288, 21096-21104.


Estarás C, Fueyo R, Akizu N,  Beltrán S, Martínez-Balbás MA. RNA polymerase progression through H3K27me3-enriched gene bodies require JMJD3 histone demethylase. (2013) Molecular Biology of the Cell, 24, 351-360.  .- Highligted in MBC


Asensio-Juan E, Gallego C, Martínez-Balbás MA. Histone demethylase PHF8 is essential for cytoskeleton dynamics. (2012) Nucleic Acis Research, 40, 9429-9440.


Estarás C, Akizu N,  García MA, de la Cruz X, Martínez-Balbás MA. Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program.  (2012) Development, 139, 2681-2691.


Celià T, Meca-Cortés O, Martínez-Paz A, Mateo F, Ulloa C, Rubio N, Arnal A, Estarás C, Lozano JJ,  Bermudo R,  García de Herreros A, Martínez-Balbás MA, Millà J, Vilella R, Gomis R, Blanco -Fernández PL, Thomson TM. Epithelial-mesenchymal transition can suppress major attributes of epithelial tumor-initiating cells. (2012) Journal of Clinical Investigation, 122, 1849-1868.


Perez-Luna M, Aguasca M, Perearnau A, Serratosa J, Martínez-Balbás MA, Pujol MJ Bachs O. PCAF regulates the stability of the transcriptional regulator and cyclin-dependent kinase inhibitor Regulation of p27Kip1.  (2012) Nucleic Acid Research, 40, 6520-6533.


Akizu, N, Estarás C, Guerrero L, Martí E, Martínez-Balbás MA. H3K27me3 regulates BMP activity in developing spinal cord.  (2010) Development, 137, 2915-2925. Highligted in Development 137:e1702: “Spinal cord development BuMPs into chromatin” and Published in Articles of Interest in Other COB Journals – From Development (2010). J Cell Sci  123:e1; doi:10.1242/jcs.079251


Lois S, Akizu N, Martínez-Balbás MA, de la Cruz X. Characterization of structural variability sheds light on the specificity determinants of the interaction between effector domains and histone tails. (2010) Epigenetics, 5, 137-148. *COVER PICTURE


Mateo F, Vidal-Laliena M, Canela N, Zecchin A, Martínez-Balbás MA, Agell, N, Giacca M, Pujol MJ, Bachs O. The transcriptional co-activator PCAF regulates cdk2 activity .(2009) Nucleic Acids Reseach, 37, 7072-7084.


Mateo F, Vidal-Laliena M, Canela N, Busino L, Martínez-Balbás MA, Pagano M, Agell N, Bachs O. Degradation of cyclin A is regulated by acetylation. (2009) Oncogene, 28, 2654-2666.


Blanco-García N, Asensio-Juan E, de la Cruz X,  Martínez-Balbás MA. Autoacetylation regulates P/CAF nuclear localization. (2009) J.  Biol. Chem , 284, 1343-1352.


Valls E, Blanco N, Aquizu N, Piedra D, Estarás C, de la Cruz X, Martínez-Balbás MA. Involvement of chromatin and histone deacetylation in the SV40 T antigen transcription regulation. (2007) Nucleic Acids Research, 35, 1958-1968.


 LLois S, Blanco N, Martínez-Balbás MA*, de la Cruz X*.  Patterns of alternative splicing in chromatin-modifying enzymes unveil a  new complexity level in the regulation of gene expression (2007) BMC Genomics, 8, 252-266. *CO-CORRESPONDING AUTHOR


Sánchez-Molina S, Oliva JL, García-Vargas S, Valls E, Rojas JM, Martínez-Balbás, MA. The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway. (2006) Biochem J, 398, 215-224.


De la Cruz X, Llois S, Sánchez-Molina S, Martínez-Balbás MA. Do protein motifs read the histone code? (2005) BioEssays, 27 (2) 164-175.


Valls E, Sánchez-Molina S, Martínez-Balbás MA. Role of histone modifications in marking and activating genes through mitosis. (2005) J. Biochem. Chem, 280, 42592-42600.


Valls E, de la Cruz X, Martínez-Balbás MA. The SV40 T antigen modulates CBP histone acetyltransferase activity. (2003) Nucleic Acids Research, 31, 3114-3122.


Santos-Rosa H,  Valls E, Kouzarides T, Martínez-Balbás MA. Mechanisms of P/CAF auto-acetylation. (2003) Nucleic Acids Research, 31, 4285-4292.


Martínez-Balbás MA, Bauer UM, Nielsen SJ, Brehm A,  Kouzarides T. Regulation of E2F1 activity by acetylation. (2000) EMBO J, 19, 662-671.


Martínez-Balbás MA, Tsukiyama T,  Wu C. Drosophila NURF-55 a WD repeat protein common to CAF-1 and related to components of histone modifying enzymes. (1998) PNAS,  95, 132-137.


Wu C, Tsukiyama T, Gdula D, Georgel P, Martínez-Balbás MA, Mizuguchi G, Ossipow V, Sandaltzopoulos R,  Wang HM. ATP-dependent Remodeling of Chromatin. (1998) Cold Spring Harbor Symposia on quantitative Biology. Vol LXIII, 525-534.


Martínez-Balbás MA, Bannister A, Martin K, Haus-Seuffert P, Meisterernst M,  Kouzarides T. The CBP histone acetyltransferase activity stimulates transcripcion. (1998) EMBO J, 17, 2886-2893.


Reid J, Bannister A, Zegerman P, Martínez-Balbás MA, Kouzarides T. E1A directly binds and regulates the P/CAF acetyltransferase. (1998) EMBO J, 17, 4469-4477.


Espinás ML, Jiménez-García E, Martínez-Balbás MA, Azorín F. Formation of triple-stranded DNA at d(GA.TC)n sequences prevents nucleosome assembly and is hindered by nucleosomes. (1996) J.  Biol. Chem , 271, 31807-31812.


Martínez-Balbás MA, Jiménez-García E,  Azorín F. Zinc selectively interacts with DNA sequences essential for the binding of the zinc finger transcription factor TFIIIA to the 5S-RNA gene. (1995) Nucleic Acids Research,  23, 2464-2471.


Martínez-Balbás MA, Dey A, Rabindran SR, Ozato K,  Wu C. Displacement of sequence-specific transcription factors from mitotic chromatin. (1995) Cell,  83, 29-38.


Martínez-Balbás MA. Reversion of a SV40 enhancer mutant depends on the growth conditions. (1994) Gene, 139, 211-214.


Beltrán R,* Martínez-Balbás MA*, Bernues J, Murdrie A, Lilley D, Azorín F. Characterization of the zinc-induced transition to H*-DNA at a d(CT/GA)22 sequence. (1993) J. Mol. Biol, 230, 966-978. * EQUALLY CONTRIBUTING AUTHORS


Martínez-Balbás MA, Azorín F. The effect of zinc on the secondary structure of the d(GA.CT)n DNA sequences of different length: a model for the formation H*-DNA. (1993) Nucleic Acids Research, 21, 2557-2562.


De la Cruz X, Martínez-Balbás MA, Tormo J, Verdaguer N. Crystal and Molecular structure of 2-oxo-1-Pyrrolidine Acetamide Copper Perchlorate Monohydrate. (1992) Acta Cryst, C48, 118-121.


Azorín F, Beltrán R, Casasnovas JM, Bernues J, Martínez-Balbás MA, Huertas A,  Ortiz M. Structural polymorphism of d(CT/GA)n sequences: The effect of zinc ions. (1992) J. Cellular Biochemistry,  16E, 126, R 101.


Carrera P, Martínez-Balbás MA, Portugal  J, Azorín F. Identification of sequence elements contributing to the intrinsic curvature of the mouse satellite DNA repeat. (1991) Nucleic Acid Research 19, 5639-5644.


Martínez-Balbás MA, Rodríguez-Campos A, García-Ramirez M, Saínz J, Carrera P, Aymamí J, Azorín F. Satellite DNA contain sequences which induce curvature. (1990) Biochemistry, 29, 2342-2348.


Pons M, Campayo L, Martínez-Balbás MA, Azorín F, Navarro P, Giralt E. A new ionizable chromophore of 1,4-bis (alkylamino) benzo (G) phthalazine which interacts with DNA by intercalation. (1990) J. of Medical Chemistry, 34, 82-86.


Casasnovas JM, Ellison MJ, Rodríguez-Campos A, Martínez-Balbás MA, Azorín F. In vivo  assesment of the Z-DNA forming potenetial of (CG)n and (CA)n sequences cloned into SV40 minichromosomes. (1989) J. Mol. Biol,  208, 537-549.


 

Project funding

RESEARCH GRANTS


Chromatin activity and homeostasis in neural stem cells: characterization of the role histone demethylases PHF2 and JMJD3. PGC2018-096082-B-I00

  • Spanish Ministry for Science and Innovation
  • From: 01/01/2019 To: 31/12/2021
  • Principal Investigator: Marian Martínez-Balbás


Impact of the histone demethylases JMJD3 and PHF8 in the function of neural stem cells, early neurogenesis and their implications in intellectual disability. BFU2015-69248

  • Spanish Ministry for Science and Innovation
  • From: 01/01/2016 To: 31/12/2018
  • Principal Investigator: Marian Martínez-Balbás


Epigenetic deffects associated to mental retardation. Fondation Jérôme Lejeune. 2015

  • Fondation Jérôme Lejeune
  • From: 01/08/2016 To: 31/07/2017
  • Principal Investigator: Marian Martínez-Balbás


Epigenetic control of neurogenesis: Role of histone demethylases JMJD3 and PHF8. BFU2012-34261

  • Spanish Ministry for Economy and competitivity
  • From: 01/01/2013 To: 31/12/2015
  • Principal Investigator: Marian Martínez-Balbás


Epigenetic deffects associated to mental retardation. Fondation Jérôme Lejeune. 2012

  • Fondation Jérôme Lejeune
  • From: 9/09/2012 To: 9/09/2014
  • Principal Investigator: Marian Martínez-Balbás


Epigenetic deffects involved in mental retardation. 09 0210

  • La Marató de TV3 Fondation.
  • From: 19/11/2009 To: 19/11/2012
  • PI: Marian Martínez-Balbás


Genomica estructural i aplicada SRG2009

  • Generalitat de Catalunya.
  • From: 12/2009 To: 12/2014
  • Coordinator: Joaquín Roca


Epigenetic mechanisms involved in cellular proliferation and differentiation: histone methylation/demethylation role. BFU2009-11144

  • Spanish Ministry for Science and Education.
  • From: 12/2009 To: 12/2012
  • PI: Marian Martínez-Balbás

 


Epigenetic mechanisms involved in cellular proliferation and differentiation: histone modification role. BFU2006-01493

  • Spanish Ministry for Science and Education
  • From: 1/10/2006 To: 30/09/2009
  • PI: Marian Martínez-Balbás

 


Epigenetics: mechanisms and disease. Consolider Ingenio. CSD2006-00049

  • Spanish Ministry for Science and Education
  • From 11/2006 To: 11/2011
  • Coordinator: Miguel Beato Rosal PI: Marian Martínez-Balbás

 


Chromatin: structural and functional analysis.

  • Generalitat de Catalunya.
  • From: 1/1/2006 To: 1/1/2008
  • Coordinator: Ferrán Azorín Marín PI: Marian Martínez-Balbás


Role of acetylation in the cell cycle control. SAF2005-01285

  • Spanish Ministry for Science and Education
  • From: 12/2005 To: 12/2006
  • PI: Marian Martínez-Balbás

 


Structural genomics: proteins and related protein complexes. GEN2003-20642

  • Spanish Ministry for Science and Education
  • From: 1/9/2004 To:1/9/2007
  • Coordinator: Miquel Coll


Role of acetylation in the cell cycle control and in the Ras-induced cell transformation. SAF2002-00741

  • Spanish Ministry for Science and Education
  • From: 12/2002 To: 12/2005
  • PI: Marian Martínez-Balbás


Control of gene expression by acetylation. PB98-0468

  • Spanish Ministry for Science and Education
  • From: 1/12/1999 To 1/12/2002
  • PI: Marian Martínez-Balbás

Vacancies/Jobs

PREDOCTORAL POSITION IN EPIGENETICS 

PREDOCTORAL POSITION IN EPIGENETICS A predoctoral position is available to work on epigenetics and neurogenesis.…

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OFERTA DE CONTRATO PREDOCTORAL 

OFERTA DE CONTRATO PREDOCTORAL Se ofrece contrato predoctoral para trabajar en el Instituto de Biología…

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