Montse Gustems - Academia.edu (original) (raw)

Papers by Montse Gustems

Mammalian Genome

Over the last decade, INFRAFRONTIER has positioned itself as a world-class Research Infrastructur... more Over the last decade, INFRAFRONTIER has positioned itself as a world-class Research Infrastructure for the generation, phenotyping, archiving, and distribution of mouse models in Europe. The INFRAFRONTIER network consists of 22 partners from 15 countries, and is continuously enhancing and broadening its portfolio of resources and services that are offered to the research community on a non-profit basis. By bringing together European rodent model expertise and providing valuable disease model services to the biomedical research community, INFRAFRONTIER strives to push the accessibility of cutting-edge human disease modelling technologies across the European research landscape. This article highlights the latest INFRAFRONTIER developments and informs the research community about its extensively utilised services, resources, and technical developments, specifically the intricacies of the INFRAFRONTIER database, use of Curated Disease Models, overview of the INFRAFRONTIER Cancer and Rar...

CERN European Organization for Nuclear Research - Zenodo, Apr 20, 2022

c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA

This article cites 69 articles, 58 of which can be accessed free

The role of NF-B in regulating human cytomegalovirus (HCMV) replication and gene transcription re... more The role of NF-B in regulating human cytomegalovirus (HCMV) replication and gene transcription remains controversial. Multiple, functional NF-B response elements exist in the major immediate-early promoter (MIEP) enhancer of HCMV, suggesting a possible requirement for this transcription factor in lytic viral replication. Here we demonstrate by generating and analyzing HCMVs with alterations in the MIEPenhancer that, although this region is essential for HCMV growth, none of the four NF-B response elements contained within the enhancer are required for MIE gene expression or HCMV replication in multiple cell types. These data reveal the robustness of the regulatory network controlling the MIEP enhancer.

Nucleic Acids Research, 2021

In infected cells, Epstein–Barr virus (EBV) alternates between latency and lytic replication. The... more In infected cells, Epstein–Barr virus (EBV) alternates between latency and lytic replication. The viral bZIP transcription factor ZEBRA (Zta, BZLF1) regulates this cycle by binding to two classes of ZEBRA response elements (ZREs): CpG-free motifs resembling the consensus AP-1 site recognized by cellular bZIP proteins and CpG-containing motifs that are selectively bound by ZEBRA upon cytosine methylation. We report structural and mutational analysis of ZEBRA bound to a CpG-methylated ZRE (meZRE) from a viral lytic promoter. ZEBRA recognizes the CpG methylation marks through a ZEBRA-specific serine and a methylcytosine-arginine-guanine triad resembling that found in canonical methyl-CpG binding proteins. ZEBRA preferentially binds the meZRE over the AP-1 site but mutating the ZEBRA-specific serine to alanine inverts this selectivity and abrogates viral replication. Our findings elucidate a DNA methylation-dependent switch in ZEBRA’s transactivation function that enables ZEBRA to bind ...

Journal of Virology, 2015

The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus ... more The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodes LMP2A , one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genes K1 or K15 in lieu of LMP2A and infected primary BCR-negative (BCR − ) human B cells with them. We confirmed that the survival of BCR – B cells and their proliferation depended on an a...

Nucleic Acids Research, 2013

CpG methylation in mammalian DNA is known to interfere with gene expression by inhibiting the bin... more CpG methylation in mammalian DNA is known to interfere with gene expression by inhibiting the binding of transactivators to their cognate sequence motifs or recruiting proteins involved in gene repression. An Epstein–Barr virus-encoded transcription factor, Zta, was the first example of a sequence-specific transcription factor that preferentially recognizes and selectively binds DNA sequence motifs with methylated CpG residues, reverses epigenetic silencing and activates gene transcription. The DNA binding domain of Zta is homologous to c-Fos, a member of the cellular AP-1 (activator protein 1) transcription factor family, which regulates cell proliferation and survival, apoptosis, transformation and oncogenesis. We have identified a novel AP-1 binding site termed meAP-1, which contains a CpG dinucleotide. If methylated, meAP-1 sites are preferentially bound by the AP-1 heterodimer c-Jun/c-Fos in vitro and in cellular chromatin in vivo. In activated human primary B cells, c-Jun/c-Fo...

Journal of Virology, 2005

The major immediate-early (MIE) genes of cytomegaloviruses (CMV) are broadly thought to be decisi... more The major immediate-early (MIE) genes of cytomegaloviruses (CMV) are broadly thought to be decisive regulators of lytic replication and reactivation from latency. To directly assess the role of the MIE protein IE1 during the infection of murine CMV (MCMV), we constructed an MCMV with exon 4 of the ie 1 gene deleted. We found that, independent of the multiplicity of infection, the resulting recombinant virus, MCMVdie1, which fails to express the IE1 protein, was fully competent for early gene expression and replicated in different cultured cell types with identical kinetics to those of parental or revertant virus. Immunofluorescence microscopy studies revealed that MCMVdie1 was greatly impaired in its capacity to disrupt promyelocytic leukemia bodies in NIH 3T3 cells early after infection, a process that has been proposed to increase viral transcription efficiency. We examined MCMVdie1 in the murine model using both immunocompetent BALB/c and severe combined immunodeficient (SCID) mi...

Journal of Virology, 2006

The role of NF-κB in regulating human cytomegalovirus (HCMV) replication and gene transcription r... more The role of NF-κB in regulating human cytomegalovirus (HCMV) replication and gene transcription remains controversial. Multiple, functional NF-κB response elements exist in the major immediate-early promoter (MIEP) enhancer of HCMV, suggesting a possible requirement for this transcription factor in lytic viral replication. Here we demonstrate by generating and analyzing HCMVs with alterations in the MIEP-enhancer that, although this region is essential for HCMV growth, none of the four NF-κB response elements contained within the enhancer are required for MIE gene expression or HCMV replication in multiple cell types. These data reveal the robustness of the regulatory network controlling the MIEP enhancer.

Journal of Virology, 2008

The human cytomegalovirus (HCMV) major immediate-early enhancer has been postulated to play a piv... more The human cytomegalovirus (HCMV) major immediate-early enhancer has been postulated to play a pivotal role in the control of latency and reactivation. However, the absence of an animal model has obstructed a direct test of this hypothesis. Here we report on the establishment of an in vivo, experimentally tractable system for quantitatively investigating physiological functions of the HCMV enhancer. Using a neonate BALB/c mouse model, we show that a chimeric murine CMV under the control of the HCMV enhancer is competent in vivo, replicating in key organs of mice with acute CMV infection and exhibiting latency/reactivation features comparable for the most part to those of the parental and revertant viruses.

Journal of Virology, 2010

Human cytomegalovirus (HCMV) infection causes a rapid induction of c-Fos and c-Jun, the major sub... more Human cytomegalovirus (HCMV) infection causes a rapid induction of c-Fos and c-Jun, the major subunits of activator protein 1 (AP-1), which in turn have been postulated to activate the viral immediate-early (IE) genes. Accordingly, the major IE promoter (MIEP) enhancer, a critical control region for initiating lytic HCMV infection and reactivation from the latent state, contains one well-characterized AP-1 site and a second candidate interaction site. In this study we explored the role of these AP-1 elements in the context of the infection. We first show that the distal candidate AP-1 motif binds c-Fos/c-Jun heterodimers (AP-1 complex) and confers c-Fos/c-Jun-mediated activity to a core promoter. Site-directed mutagenesis studies indicate that both AP-1 response elements are critical for 12- O -tetradecanoylphorbol-13-acetate (TPA)-enhanced MIEP activity in transient-transfection assays. In marked contrast to the results obtained with the isolated promoter, disruption of the AP-1 re...