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Qualai J.,Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol | Li L.-X.,University of Arkansas for Medical Sciences | Cantero J.,Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol | Tarrats A.,University Hospital Germans Trias i Pujol | And 5 more authors.
PloS one | Year: 2016

CD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential.


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 8 more authors.
Molecular and Cellular Biology | Year: 2012

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.


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 | Year: 2011

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.


PubMed | Institute for Predictive and Personalized Medicine of Cancer IMPPC, University of Arkansas for Medical Sciences, Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol, Autonomous University of Barcelona and 4 more.
Type: Journal Article | Journal: PloS one | Year: 2016

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. 47 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 41 and 47 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.


PubMed | Institute for Predictive and Personalized Medicine of Cancer IMPPC, University of Arkansas for Medical Sciences, Institute Dinvestigacio En Ciencies Of La Salut Germans Trias I Pujol, Barcelona Institute for Research in Biomedicine and 2 more.
Type: Journal Article | Journal: PloS one | Year: 2016

CD11c is an integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from nave mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including T cells and invariant natural killer T (iNKT) cells. However, in women, only T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)- secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential.


PubMed | Institute for Predictive and Personalized Medicine of Cancer IMPPC, Hospital CIMA Sanitas, Royal Infirmary and Health science Research Institute of the Germans Trias i Pujol Foundation IGTP
Type: | Journal: Scientific reports | Year: 2016

Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. De-regulation of the NF-B signalling pathway has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-B was hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-B inhibitor. The concomitant combination of Curcumin+OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion of their resistant phenotype, through the inhibition of the NF-B signalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-B-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells that were more efficiently down-regulated after OXA+Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-B pathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastases was associated with response to OXA+Curcumin. In conclusion, we suggest that combination of OXA+Curcumin could be an effective treatment, for which CXCL1 could be used as a predictive marker, in CRC patients.


Creppe C.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Posavec M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Douet J.,Institute for Predictive and Personalized Medicine of Cancer IMPPC | Buschbeck M.,Institute for Predictive and Personalized Medicine of Cancer IMPPC
Epigenomics | Year: 2012

The importance of epigenetic mechanisms is most clearly illustrated during early development when a totipotent cell goes through multiple cell fate transitions to form the many different cell types and tissues that constitute the embryo and the adult. The exchange of a canonical H2A histone for the 'repressive' macroH2A variant is one of the most striking epigenetic chromatin alterations that can occur at the level of the nucleosome. Here, we discuss recent data on macroH2A in zebrafish and mouse embryos, in embryonic and adult stem cells and also in nuclear reprogramming. We highlight the role of macroH2A in the establishment and maintenance of differentiated states and we discuss its still poorly recognized function in transcriptional activation. © 2012 Future Medicine Ltd.


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 | Year: 2013

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.


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
Epigenetics | Year: 2010

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.


PubMed | Institute for Predictive and Personalized Medicine of Cancer IMPPC and Autonomous University of Barcelona
Type: Journal Article | Journal: Genome announcements | Year: 2015

We present here the draft genome sequences of two Mycobacterium setense strains. One of them corresponds to the M.setense type strain DSM-45070, originally isolated from a patient with a posttraumatic chronic skin abscess. The other one corresponds to the nonpathogenic M.setense strain Manresensis, isolated from the Cardener River crossing Manresa, Catalonia, Spain. A comparative genomic analysis shows a smaller genome size and fewer genes in M.setense strain Manresensis relative to those of the type strain, and it shows the genome segments unique to each strain.

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