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Chromatin Biology

imatge Central Grup Recerca

Scientific Team

Researchers
Alex Vaquero, Laia Bosch, Anna Marazuela
Postdoctoral researchers
Pau Castillo
Predoctoral researchers
Maria dolores Espinosa, George Rasti, Irene Santos, Nuria Sima, Nicolas Simonet
Master and grade students
Jèssica González

Introduction

Cell life regulation is determined by the information encoded in nuclear DNA. In Eukaryotic cells, DNA is associated with histones to form chromatin. Among the different regulatory levels that participate in the management of DNA information, post-translational modifications of the N-terminal tails of histones are important for ensuring a proper control of chromatin functions. These modifications are in part epigenetic, which means that they can be transmitted to its progeny and in many cases are vital for the maintenance of proper cell memory. Alteration of this epigenetic information has remarkable consequences in a wide number of human pathologies, such as cancer and others. Among these modifications, Acetylation and Methylation of Lysine residues are particularly important for the regulation of Chromatin structure and Gene expression.

The main goal of our laboratory is to understand the mechanisms that rule Chromatin dynamics and in particular how these post-translational modifications interplay with the rest of chromatin machinery to keep a healthy and efficient Chromatin organization. Because of that, we are also interested in the functional implications of these mechanisms in cancer and aging. For that purpose, our lab uses a combination of Biochemistry, Molecular and Cell Biology techniques to gain insight into Chromatin Biology.

In particular, our studies focus in a group of proteins, the Sir2 family or Sirtuins, that are homologues of the yeast silencing factor Sir2, a NAD+-dependent deacetylase involved in many aspects of chromatin regulation such as epigenetic silencing, DNA repair and replication, DNA recombination, etc... Two features make particularly interesting the Sir2 family: First, the requirement of the metabolic redox cofactor NAD+ for the enzymatic activity of the family, allows their members to act as sensors of cell metabolism.

Second, members of this family show a close link with the regulation of a specific modification, acetylation of lysine 16 in histone H4 (H4K16Ac), involved in many functions from Chromatin structure, gene expression and cancer to many epigenetic processes through evolution. However, not all Sirtuins are deacetylases, and in fact some show instead a mono-ADP-rybosyltransferase activity.

Sirtuins have been linked to many human pathologies such as cancer, neurological diseases like Alzheimer or Parkinson´s, malaria, leishmaniosis, and hormone-related pathologies. However, the mechanisms by which these proteins are involved in these processes are relatively unknown.

In our lab we aim to characterize the role of Sirtuins in chromatin regulation and the functional implications of this role on cancer, cell viability and genome integrity. From the seven mammalian Sirtuins (SirT1-7), only SirT1, 2, 6, 7 and possibly 3 seem to be functionally linked to Chromatin. Interestingly, each of them is involved in a particular aspect of chromatin regulation different from the others. Our main lines of research are actually defined by each of these Sirtuins and their corresponding specific role on chromatin.



Research lines

. Sirtuins in genome organization and chromatin structure (SirT1)

. Sirtuins  and cell cycle control  (SirT2)

. Sirtuins and DNA repair  (SirT6)

. Sirtuins and nucleolar function  (SirT7)


Selected papers

 

Pérez-Montero, S, Carbonell, A, Moran, T, Vaquero, A, Azorin, F. The early embryonic and germ line specific linker histone H1 variant of Drosophila, dBigH1, regulates zygotic genome activation. Dev. Cell. 26(6):578-590 (2013)

 

 

Bosch-Presegué, L, Vaquero A. Sirtuins in stress response: Guardians of the genome. Oncogene 33(29):3764-75. (2014)

 

Sima, N., Bosch-Presegué, L., Vaquero, A. Sirtuins as a double-edged sword in cáncer: From Molecular mechanisms to Therapeutic opportunities. Stress response pathways in cancer (Ed. Georg Wondrack). Springer (US). I.S.B.N. 978-94-017-9420-6 (2014) 

 

-Bosch-Presegué, Vaquero A.  Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity. FEBS J. Sep 15. doi: 10.1111/febs.13053. [Epub ahead of print](2014)

Martínez-Redondo, P, Vaquero A . Methods to Study the Role of Sirtuins in Genome Stability. Issue on SIRTUINs. METHODS IN MOLECULAR BIOLOGY. (Ed. Matthew Hershey) 1077:273-83. (2013)

 

 

Martínez-Redondo, P, Vaquero, A. The Diversity of Histone Versus Nonhistone Sirtuin Substrates. Genes & Cancer 4(3-4):148-63(2013)

 

Serrano, L*, Martínez-Redondo, P*, Marazuela-Duque, A, Vazquez, BN, Kane-Goldsmith, N, Dooley, SJ, Tong, Q, Rabanal, RM, Fondevila, D, Muñoz, P, Tischfield, JA, Vaquero, A. The tumor supressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes & Dev.27(6):639-53.  (2013)

 

Kuhlmann, B,  Modlich, U, Schienke, A, Wolf, S, Skawran, B, Büsche, G, Kreipe, H, Baum, C, Santos-Barriopedro, I, Vaquero, A,  Schlegelberger, B, Rudolph, C. Histone methyltransferase Suv39h1 deficiency prevents c-Myc-induced chromosomal instability in murine myeloid leukemias.  Genes, Chromosomes and Cancer. 52(4):423-30. (2013)

 

Cortes, A., Crowley, V.M., Vaquero, A, Voss, T.S. A view on the role of Epigenetics in the Biology of Malaria Parasites.  PLOS Pathogens. 8(12): e1002943. doi:10.1371/journal.ppat.1002943 (2012)

 

Martínez-Redondo, P., Santos-Barriopedro, I., Vaquero A . A Big Step for SIRT7, One Giant Leap for Sirtuins… in Cancer. Cancer Cell. 21(6):719-721 (2012)

 

Bonet-Costa, C., Vilaseca, M., Diema, C., Vujatovic, O, Vaquero, A,  Omeñaca, N, Castejón, L,  Bernués, J, Giralt, E,  Azorin, F.  Combined bottom-up and top-down mass spectrometry analysis identifies multiple post-translational modifications in Drosophila melanogaster linker histone H1. J. Proteomics. 75(13):4124-4138.  (2012)

 

Vujatovic, O, Zaragoza, K, Vaquero, A,  Reina, O, Bernués, J, Azorin, F.  Drosophila melanogaster linker histone dH1 is required for transposon silencing and to preserve genome integrity. Nucleic Acids Res.  40(12):5402-14  (2012)

 

Bosch-Presegue, L., Vaquero A . The dual role of Sirtuins in cancer.  Genes & Cancer. 2(6):648-662. (2011)

 

Bosch-Presegue L., Raurell-Vila H., Marazuela-Duque A., Kane-Goldsmith N., Valle A., Oliver J., Serrano L., Vaquero A. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell. 42 (2):210-223 (2011)

 

Baur,J.A., Chen, D., Chini, E.N., Chua, K., Cohen, H.Y., de Cabo, R., Deng, C., Dimmeler, S., Gius, D., Guarente, L.P., Helfand, S.L., Imai, S.I,  Itoh, H., Kadowaki, T., Koya, D., Leeuwenburgh, C.,  McBurney, M., Nabeshima,Y.-I., Neri, C., Oberdoerffer, P., Pestell, R.G., Rogina, B., Sadoshima, J., Sartorelli, V., Serrano, M., Sinclair, D.A., Steegborn, C., Tatar, M., Tissenbaum, H.A., Tong, Q., Tsubota, K., Vaquero, A., Verdin, E. Dietary Restriction: Standing Up for Sirtuins. Science 329: 1012-1013 (2010)

imatge personal
 

Group leader

Alex Vaquero
Telephone  
+34 932607248
E-mail  
avaquero@idibell.cat
 
© 2017 Institut d'Investigació Biomèdica de Bellvitge



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