▷ Molecular Signaling and Chromatin Research Group

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.

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.

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.

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.

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

Lab people

Marian Martínez

Senior Research Scientist CSIC

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.

Marta Artés

PhD Student

Samuel Aguirre

PhD Student

Monica Barrios Lopez

Masters Student

Past students

Stella Pappa

PhD Student

Simona Iacobucci

PhD Student

Marta Vicioso

PhD Student

Elena Álvarez de la Campa

PhD Student

Raquel Fueyo

PhD Student

Maria Alejandra Garcia

PhD Student

Arnau Noguera Segura

University Student (JAE Intro Programme)

Selected publications

View all publications

Gracia-Diaz C et al (2023) Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders. Nature Communications, 14(1):4109. doi: 10.1038/s41467-023-39645-5.

https://www.nature.com/articles/s41467-023-39645-5

Vicioso-Mantis M, Martínez-Balbás MA (2022). Spatial genome organization, TGFβ, and biomolecular condensates: Do they talk during development? BioEssays 17:e2200145. DOI: 10.1002/bies.202200145

http://doi.wiley.com/10.1002/bies.202200145

Vicioso-Mantis M, Aguirre S, Martínez-Balbás MA. JmjC family of histone demethylases form nuclear condensates. International Journal of Molecular Sciences. 2022, 23(14):7664. doi: 10.3390/ijms23147664.

https://www.mdpi.com/1422-0067/23/14/7664

Vicioso-Mantis M^*, Fueyo R^*, Navarro C, Cruz-Molina S, van Ijcken W FJ, Rebollo E, Rada-Iglesias A, and Martínez-Balbás MA (2022) JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation. Nature Communications. 13(1):3263.

https://www.nature.com/articles/s41467-022-30614-y

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/

View all publications

All publications

View selected publications

https://www.nature.com/articles/s41467-023-39645-5

https://www.mdpi.com/1422-0067/23/14/7664

Vicioso-Mantis M *, Fueyo R*, Navarro C, Cruz-Molina S, van Ijcken W FJ, Rebollo E, Rada-Iglesias A, and Martínez-Balbás MA (2022) JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation. Nature Communications. 13(1):3263.

https://www.nature.com/articles/s41467-022-30614-y

http://doi.wiley.com/10.1002/bies.202200145

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

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

https://elifesciences.org/articles/37267

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

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

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.

https://doi.org/10.18632/oncotarget.20698

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.

https://doi.org/10.1016/B978-0-12-802389-1.00010-1

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

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

https://doi.org/10.1080/23262133.2016.1250034

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

https://doi.org/10.1007/s00441-014-1924-7

Petazzi P,* Akizu N,* García MA, Estarás C, Martínez de Paz A, Rodriguez-Paredes M, Martínez-Balbás MA, Huertas D, Esteller M. An increase in MECP2 dosage impairs neural tube formation. (2014) Neurobiology of Disease, 67:49-56. * Equally contributing authors

https://doi.org/10.1016/j.nbd.2014.03.009

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

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

https://doi.org/10.1074/jbc.m113.458323

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

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

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.

https://doi.org/10.1172/jci59218

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.

https://doi.org/10.1093/nar/gks343

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). Journal of Cell Science 123:e1; doi:10.1242/jcs.079251

https://doi.org/10.1242/dev.049395

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

https://doi.org/10.4161/epi.5.2.11079

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.

https://doi.org/10.1093/nar/gkp777

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.

https://doi.org/10.1038/onc.2009.127

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

https://doi.org/10.1074/jbc.m806075200

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.

https://doi.org/10.1093/nar/gkl1113

LLois S, Blanco N, Martínez-Balbás MA*, de la Cruz X*. The functional modulation of epigenetic regulators by alternative splicing (2007) BMC Genomics, 8, 252-266. *CO-CORRESPONDING AUTHOR

https://doi.org/10.1186/1471-2164-8-252

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) Biochemical Journal, 398, 215-224.

https://doi.org/10.1042/BJ20060052

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.

https://doi.org/10.1002/bies.20176

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

https://doi.org/10.1074/jbc.M507407200

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.

https://doi.org/10.1093/nar/gkg418

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

https://doi.org/10.1093/nar/gkg655

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

https://doi.org/10.1093/emboj/19.4.662

Martínez-Balbás MA, Tsukiyama T, Wu C. Drosophila NURF-55, a WD repeat protein involved in histone metabolism. (1998) PNAS, 95, 132-137.

https://doi.org/10.1073/pnas.95.1.132

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.

http://symposium.cshlp.org/content/63/525

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

https://doi.org/10.1093/emboj/17.10.2886

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

https://doi.org/10.1093/emboj/17.15.4469

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) Journal of Biological Chemistry , 271, 31807-31812.

https://doi.org/10.1074/jbc.271.50.31807

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.

https://doi.org/10.1093/nar/23.13.2464

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.

https://doi.org/10.1016/0092-8674(95)90231-7

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

https://doi.org/10.1016/0378-1119(94)90757-9

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

https://doi.org/10.1006/jmbi.1993.1213

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.

https://doi.org/10.1093/nar/21.11.2557

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) Journal of 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.

https://doi.org/10.1093/nar/19.20.5639

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.

https://doi.org/10.1021/bi00461a019

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.

https://doi.org/10.1021/jm00105a014

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.

https://doi.org/10.1016/0022-2836(89)90146-0

View selected publications

Project funding

RESEARCH GRANTS

Investigando el papel de las desmetilasas de histonas phf2 y jmjd3 proporcionando información transcripcional, metabólica y estructural en células madre neurales. PID2021-125862NB-I00

Spanish Ministry for Science and Innovation
From: 01/09/2022 Duration: 3 years
Principal Investigator: Marian Martínez-Balbás

Proyecto PID2021-125862NB-I00 financiado por:

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

Proyecto PGC2018-096082-B-I00 financiado por:

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

Proyecto BFU2015-69248 financiado por:

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