Laboratori de biologia de la cromatina

ICO - German Trias i Pujol

Telephones:

Office (+34)-935572800 ext 4240
Lab    (+34)-935572800 ext 4241

Josep Carreras Leukaemia Research Institute
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
Spain

 
Directions

Summary

Among the greatest challenges facing organisms is how to detect and efficiently respond to life-threatening environmental changes (including nutrient deprivation) which are intimately associated to metabolic fluctuations and certain forms of stress (e.g. oxidative or genotoxic). The response to these stress conditions has a major impact in the maintenance of genome integrity and is intimately linked to the onset of many human pathologies, including cancer, endocrine disorders and cardiovascular and neurodegenerative diseases. The onset and development of haematological pathologies like leukemia are strongly influenced by this response and therefore it may be a relevant treatment approach. Our main goal is to define the epigenetic mechanisms that rule this response and its functional implications in genome stability and cancer through a multidisciplinary approach that combines Biochemistry, Genetics, Molecular and Cell Biology. In particular, we focus our studies on the sirtuin family of proteins, which coordinate the response to these forms of stress.

Research

The Chromatin Biology Laboratory is recognized for its experience in the study of response mechanisms under stress conditions. In particular, the group's main objective is to define the role of the  sirtuin family of enzymes  in the regulation of genome stability and epigenetics in response to stress and their impact in cancer and aging. Although the majority of sirtuins are NAD+-dependent deacetylases, some family members also harbour a second enzymatic activity, an ADP-ribosyltransferase (ADPRT) activity. This functional duality is intriguing and is one focus of the group’s work. Sirtuins play an important role in the hematopoietic system; as they have been seen to be involved in the maintenance of hematopoietic stem cells, cell differentiation and immune response, also they are associated with the development of some types of leukemia. Since it was set up, the laboratory has described various mechanisms involved in genome stability protection and stress response (Mol Cell 2011, Genes & Dev 2013, EMBOJ 2016, Epigenetics 2017, Cel. Rep. 2017, Nat comm. 2018). The group has participated in collaborations on other epigenetic aspects associated with the control of genomic stability (Dev. Cell 2013, NAR 2017, J of Hepatology 2017, Sci Rep 2017) and has participated in the main discussions in the field of sirtuins and the stress response (Genes & Dev 2009, Science 2010, Cancer Cell 2012, Oncogene 2014, FEBS J 2015, Proteomics 2017). In its mission to understand the contribution of sirtuins to stress response and the protection of genome stability, the work of the group covers a range of research from basic aspects of sirtuin biology to the study of their contribution to the development of human pathologies, such as leukemia and aging. In this sense, the major lines of work of the group are:

1.   Understanding the enzymatic duality of sirtuins and their specific contribution to sirtuin function. In particular, we focus our efforts in the poorly understood ADPRT activity.
2.   Sirtuin-dependent mechanisms of genomic stability including constitutive heterochromatin integrity, DNA damage signalling and repair, as well as cell cycle checkpoint control.
3.   The role of sirtuins in B-cell differentiation.
4.   Functional implication of sirtuins in cancer, and in particular in the context of hematopoietic pathologies like leukemia and lymphoma.
5.   Development of new methodology to measure in vivo sirtuins activity.

Awards

2009
Sandra Ibarra Award. Fundación Sandra Ibarra. Madrid, Spain

2009
Chromatin Biology Lab recognized as “Emerging Group”. Catalonian Government. AGAUR, Generalitat de Catalunya

2014 and 2017
Chromatin Biology Lab recognized as “Consolidated Group”. Catalonian Government. AGAUR, Generalitat de Catalunya

2016-2019
Industrial Doctorate Program. Mesostetic-Pharma/UB/IDIBELL. Generalitat de Catalunya

People

Selected publications

Urdinguio, R.G., Lopez, V., Bayón, G.F., Sierra, M., García-Toraño,E., Fernandez, R., García, M., Carella, A., Cueto, P., Prieto, P., Dmitrieva, M., Santamarina, P., Mangas, C., Diaconou, E., Ferrero, C., Tejedor, J.R., Bravo, C., Bueno, C., Sanjuán, A., Rodríguez, R.M., Suarez, B., López-Larrea, C., Bernal, T., Colado, E., Balbín, M., García-Suarez, O., Chiara, M.D., Sáenz-de-Santa-María, I., Rodríguez, F., Pando-Sandoval, A., Rodrigo, L., Santos, L., Salas, A., Vallejo, J., Carrera, A.C., Rico, D., Hernández-López, I., Vayá, A., Ricart, J.M., Seto, A., Vaquero A, Sima, N., Pisano, D., Graña, O., Thomas, T., Voss, A.K., Villar-Garea, A., Deutzmann, R., Fernandez, A.F., Fraga, M.F, Menéndez P

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Nucleic Acids Res. 47(10):5016-5037 (2019). , .
Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.
Més informació
Vazquez, B.N, Thackray, J.K., Simonet, N., Chahar, S., Kane-Goldsmith, N., An, W., Xing, J.C., Verzi, M.P., Vaquero A, Tischfield, J.A., Serrano, L

SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina

Nucleic Acids Res. 47(15):7870-7885 (2019). , .
Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.
Més informació
Li, T., Garcia-Gomez, A., Morante-Palacios, O., Ciudad, L., Özkaramehmet, S., Van Dijck, E., Rodríguez-Ubreva, J., Vaquero, A. and, Ballestar E

SIRT1/2 orchestrate acquisition of DNA methylation and loss of histone H3 activating marks to prevent premature activation of inflammatory genes in macrophage

Nucleic Acids Research 48, 665–681 , .
Sirtuins 1 and 2 (SIRT1/2) are two NAD-dependent deacetylases with major roles in inflammation. In addition to deacetylating histones and other proteins, SIRT1/2-mediated regulation is coupled with other epigenetic enzymes. Here, we investigate the links between SIRT1/2 activity and DNA methylation in macrophage differentiation due to their relevance in myeloid cells. SIRT1/2 display drastic upregulation during macrophage differentiation and their inhibition impacts the expression of many inflammation-related genes. In this context, SIRT1/2 inhibition abrogates DNA methylation gains, but does not affect demethylation. Inhibition of hypermethylation occurs at many inflammatory loci, which results in more drastic upregulation of their expression upon macrophage polarization following bacterial lipopolysaccharide (LPS) challenge. SIRT1/2-mediated gains of methylation concur with decreases in activating histone marks, and their inhibition revert these histone marks to resemble an open chromatin. Remarkably, specific inhibition of DNA methyltransferases is sufficient to upregulate inflammatory genes that are maintained in a silent state by SIRT1/2. Both SIRT1 and SIRT2 directly interact with DNMT3B, and their binding to proinflammatory genes is lost upon exposure to LPS or through pharmacological inhibition of their activity. In all, we describe a novel role for SIRT1/2 to restrict premature activation of proinflammatory genes.
Més informació
Wössner N, Alhalabi Z, González J, Swyter S, Gan J, Schmidtkunz K, Zhang L, Vaquero A, Ovaa H, Einsle O, Sippl W, Jung M

Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD

Front Oncol 2020, 10 657. Epub 30 Abr 2020
Sirtuin 1 (Sirt1) is a NAD
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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1

Sci.Adv. 6(30): eaaz2590 , .
Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.
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