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Buschbeck M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Nomdedeu J.F.,University of Barcelona | Benitah S.A.,Catalan Institution for Research and Advanced Studies | Di Croce L.,Catalan Institution for Research and Advanced Studies
Nature Cell Biology

MYC proto-oncogene is a key player in cell homeostasis that is commonly deregulated in human carcinogenesis 1. MYC can either activate or repress target genes by forming a complex with MAX (ref.2). MYC also exerts MAX-independent functions that are not yet fully characterized 3. Cells possess an intrinsic pathway that can abrogate MYC,MAX dimerization and E-box interaction, by inducing phosphorylation of MYC in a PAK2-dependent manner at three residues located in its helix,loop,helix domain. Here we show that these carboxy-terminal phosphorylation events switch MYC from an oncogenic to a tumour-suppressive function. In undifferentiated cells, MYC,MAX is targeted to the promoters of retinoic-acid-responsive genes by its direct interaction with the retinoic acid receptor-α (RARα). MYC,MAX cooperates with RARα to repress genes required for differentiation, in an E-box-independent manner. Conversely, on C-terminal phosphorylation of MYC during differentiation, the complex switches from a repressive to an activating function, by releasing MAX and recruiting transcriptional co-activators. Phospho-MYC synergizes with retinoic acid to eliminate circulating leukaemic cells and to decrease the level of tumour invasion. Our results identify an E-box-independent mechanism for transcriptional regulation by MYC that unveils previously unknown functions for MYC in differentiation. These may be exploited to develop alternative targeted therapies. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Buschbeck M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | di Croce L.,University Pompeu Fabra | di Croce L.,Catalan Institution for Research and Advanced Studies

The transition of a cell from one state to another involves large changes in the organization of its chromatin. Indeed, it has become increasingly clear that modifications of the chromatin are the molecular basis of an epigenetic memory that defines cellular identity. Histone variants are likely candidates to contribute to epigenetic regulations. Genome-wide profiling of the unusual macroH2A histone variants and the identification of interacting proteins provided important clues to their molecular and physiological function. © 2010 Landes Bioscience. Source

Qualai J.,Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol Igtp | Cantero J.,Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol Igtp | Li L.-X.,University of Arkansas for Medical Sciences | Carrascosa J.M.,Autonomous University of Barcelona | And 7 more authors.

Efforts to develop vaccines that can elicit mucosal immune responses in the female genital tract against sexually transmitted infections have been hampered by an inability to measure immune responses in these tissues. The differential expression of adhesion molecules is known to confer site-dependent homing of circulating effector T cells to mucosal tissues. Specific homing molecules have been defined that can be measured in blood as surrogate markers of local immunity (e.g. α4β7 for gut). Here we analyzed the expression pattern of adhesion molecules by circulating effector T cells following mucosal infection of the female genital tract in mice and during a symptomatic episode of vaginosis in women. While CCR2, CCR5, CXCR6 and CD11c were preferentially expressed in a mouse model of Chlamydia infection, only CCR5 and CD11c were clearly expressed by effector T cells during bacterial vaginosis in women. Other homing molecules previously suggested as required for homing to the genital mucosa such as α4β1 and α4β7 were also differentially expressed in these patients. However, CD11c expression, an integrin chain rarely analyzed in the context of T cell immunity, was the most consistently elevated in all activated effector CD8+ T cell subsets analyzed. This molecule was also induced after systemic infection in mice, suggesting that CD11c is not exclusive of genital tract infection. Still, its increase in response to genital tract disorders may represent a novel surrogate marker of mucosal immunity in women, and warrants further exploration for diagnostic and therapeutic purposes. © 2016 Qualai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Creppe C.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Cantarino N.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Noguera M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Valero V.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | And 7 more authors.
Molecular and Cellular Biology

One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight into the poorly recognized function of macroH2A in transcriptional activation and demonstrate its relevance in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells. © 2012, American Society for Microbiology. Source

Posavec M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Timinszky G.,Ludwig Maximilians University of Munich | Buschbeck M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC
Cellular and Molecular Life Sciences

How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD +-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function. © 2013 Springer Basel. Source

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