Poised enhancers are key cis-regulatory elements during ESC differentiation whose activity is facilitated by Polycomb repressive complex 2

The developmental transitions occurring during embryogenesis involve spatial and temporal changes in gene expression patterns, which are largely dependent on a group of regulatory elements known as enhancers. Enhancers are short DNA sequences able to positively control the expression of their target genes in a distance and orientation independent manner. Previous studies uncovered a unique set of enhancers in pluripotent embryonic stem cells (ESCs), named “Poised Enhancers”. Poised enhancers are marked by repressive histone marks, like the trimethylation of histone three lysine 27, which is deposited by Polycomb repressive complex 2 (PRC2), and also are bound by co-activators like P300. The fact that poised enhancers display both activating and repressing features as well as evidences indicating that they are associated with genes involved in early organogenesis led us to suggest that these regulatory elements are already bookmarked in ESCs and thus primed for their future activation once the differentiation process starts. However, the functional relevance of poised enhancers and the role of their unique chromatin features remain unknown. To gain insights into these major questions, first, poised enhancers were identified in mouse embryonic stem cells (mESCs) and their activation was evaluated during the establishment of anterior neural identity. Second, using CRISPR/Cas9 technology, poised enhancer candidates were deleted in mESCs, which were then differentiated into anterior neural progenitors. In general, the poised enhancer deletions resulted in severely reduced induction of the poised enhancer’s target genes. Furthermore, circularized chromosome conformation capture coupled to sequencing experiments revealed that poised enhancers and their target genes physically interacted already in ESCs, thus preceding the activation of poised enhancers and their target genes. Interestingly, these poised enhancer-target gene interactions observed in mESCs were found to be PRC2 dependent. Additionally, it was demonstrated that while PRC2 was not necessary to maintain poised enhancers in an inactive state in mESCs, was required for the induction of the poised enhancers’ target genes upon anterior neural differentiation. Finally, poised enhancers were found to frequently reside within a high CpG-dinucleotide genomic context that can directly mediate the recruitment of PRC2. Overall, these findings demonstrate that poised enhancers are essential for the proper expression of the anterior neural developmental program. Importantly, our work illuminates an unexpected function for PRC2 in promoting neural induction. Our data demonstrates that both poised enhancers and their target genes display intrinsic sequence features that can directly mediate PRC2 recruitment. Consequently, PRC2 can bring poised enhancers and their targets into physical proximity already in mESCs, thus providing a permissive regulatory topology that we propose can facilitate the future induction of mayor anterior neural genes

Epigenetic mechanisms of Strip2 in differentiation of pluripotent stem cells

Significant evidence points to Strip2 being a key regulator of the differentiation processes of pluripotent embryonic stem cells. However, Strip2 mediated epigenetic regulation of embryonic differentiation and development is quite unknown. Here, we identified several interaction partners of Strip2, importantly the co-repressor molecular protein complex nucleosome remodeling deacetylase/Tripartite motif-containing 28/Histone deacetylases/Histone-lysine N-methyltransferase SETDB1 (NuRD/TRIM28/HDACs/SETDB1) histone methyltransferase, which is primarily involved in regulation of the pluripotency of embryonic stem cells and its differentiation. The complex is normally activated by binding of Krueppel-associated box zinc-finger proteins (KRAB-ZFPs) to specific DNA motifs, causing methylation of H3 to Lysin-9 residues (H3K9). Our data showed that Strip2 binds to a DNA motif (20 base pairs), like the KRAB-ZFPs. We establish that Strip2 is an epigenetic regulator of pluripotency and differentiation by modulating DNA KRAB-ZFPs as well as the NuRD/TRIM28/HDACs/SETDB1 histone methyltransferase complex

A New Set of in Silico Tools to Support the Interpretation of ATM Missense Variants Using Graphical Analysis

Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of pre-diction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information. (J Mol Diagn 2024, 26: 17-28; https://doi.org/10.1016/j.jmoldx.2023.09.009

A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients

Background Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. Methods Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. Results Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. Conclusions Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.FEDER funds-a way to build Europe PI19/00553 PI16/00563 PI16/01898 SAF2015-68016-RGeneralitat de Catalunya 2017SGR1282 2017SGR496CERCA Program: Government of CataloniaXunta de GaliciaInstituto de Salud Carlos III. AES PI19/00340Spanish Government SAF2016-80255-REuropean Commission EFA086/15Instituto de Salud Carlos III European Commissio

Walking family: Programme of parental skills during foster care and reunification. Summary of main findings of the Project I+D EDU2014-52921-C2. [Infographics]

Podeu consultar la versió castellana, francesa i portuguesa al recurs relacionat.Walking Family is a support programme for specific parenting skills in foster care and reunification. Its main aim is to promote the acceptance and involvement of the welfare measure and to foster and strengthen reunification. One of the most relevant aspects of the programme is its group methodology, as it can be used to convey effective coping strategies for everyday problems. Walking Family is characterised by three cornerstones of innovation: positive parenting and child welfare, child participation and family resilience. The programme is developed over 5 modules, each containing 3 sessions. Each session offers activities to do with the children, with the parents and with the family as a unit

Instrumento de Acompañamiento. El proceso de acompañamiento en situaciones de vulnerabilidad en el periodo perinatal

El documento que presentamos se centra en los procesos de acompañamiento de las mujeres y sus hijos e hijas en situación de vulnerabilidad durante el periodo perinatal. Para su elaboración se ha realizado una revisión del concepto de acompañamiento y un análisis de las diferentes herramientas de acompañamiento que utilizan los profesionales del proyecto CAPEvFAIR. La revisión teórica ha permitido enmarcar el concepto, los objetivos y los aspectos claves para desarrollar procesos de acompañamiento que contribuyen a mejorar el bienestar de este colectivo y, por ende, a reducir la vulnerabilidad. La reflexión y el debate continuado entre los investigadores universitarios y los profesionales que participan en el proyecto CAPEvFAIR han nutrido todo este proceso generando un nuevo marco donde inscribir la intervención del profesional surgido del diálogo entre teoría y práctica. Este marco del acompañamiento aporta una nueva visión de la intervención profesional centrada en el colectivo y el período específico que nos ocupa aquí. Este material puede ser utilizado por los diferentes profesionales que trabajan e intervienen en el proceso de acompañamiento durante el período perinatal de madres, hijos e hijas en situación de vulnerabilidad. El documento, a parte del marco general, ofrece diferentes instrumentos que cada profesional podrá adaptar a su contexto, a las necesidades de la población con la que interviene y a la realidad específica del país en el que se aplique. El documento que se ofrece debe interpretarse como una herramienta para orientar a los y las profesionales en su tarea de acompañamiento a este colectivo.Proyecto Europeo CapeVfair. Erasmus

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde