Uncovering the mechanisms and information content of CpG-resolved DNA methylation programming during hematopoietic differentiation

DNA methylome remodeling is an essential molecular mechanism underlying all stages of hematopoietic differentiation. However, current datasets only cover a fraction of the genome and are often limited to specific hematopoietic cell types. A comprehensive, genome-wide atlas of the DNA methylation dynamics during hematopoietic differentiation is still missing. Preliminary evidence suggests that the single-cell landscape of the hematopoietic stem and progenitor cell (HSPC) compartment is characterized by a structured continuum of epigenetically-defined cell states. Significant advances in charting this epigenetic state manifold have recently been achieved for the chromatin accessibility and histone modification layers. However, despite its potential importance, the landscape of single-cell DNA methylome states in the HSPC compartment remains largely unexplored. This project aimed to comprehensively map the genome-wide DNA methylation dynamics during hematopoietic differentiation and leverage this atlas as a reference to analyze the single-cell DNA methylome landscape in the HSPC compartment and among mature hematopoietic cells. The functional importance and rich information content of differentially methylated regions (DMRs) are well-established. However, the DNA methylation layer inherently possesses the capability to encode information at CpG resolution. The role and extent of differentially methylated CpG (DMCpG) programming within DMR regions is largely unexplored. This project therefore aimed to evaluate the role and mechanisms of DMCpG programming during hematopoietic differentiation. Using high-coverage tagmentation-based whole-genome bisulfite sequencing data for 25 hematopoietic populations, I have compiled a genome-wide, dual-layer DMR/DMCpG atlas, which maps, annotates, and integrates DMR and DMCpG programming during hematopoietic differentiation. Loss of stemness was associated with lineage-independent gain of DNA methylation, while lineage specification was accompanied by hierarchical DNA methylation dynamics, characterized by unidirectional loss of DNA methylation. Different DMCpGs within focal DMR intervals were often distinctly programmed and thus contained heterogeneous information content. In particular, most of the DMRs were seeded and progressively expanded through subsequent programming of specific DMCpGs at different stages of differentiation. Mature hematopoietic cells exhibited systematic seed DMCpG hypomethylation in DMRs associated with alternative cell fates. This seed hypomethylation likely represents epigenetic memory of alternative fate explorations in progenitor cells. Collectively, these findings suggest a hierarchical model of DNA methylation programming, in which information is encoded through DMR programming and through DMCpG programming within DMR regions. This model represents a significant extension of the commonly accepted paradigm of regional DNA methylation programming. Using the dual-layer DMR/DMCpG atlas as a reference, single-cell methylome states for 312 HSPCs, as well as for a total of 136 mature B cells, T cells, CFU-Es, and monocytes, could be dissected with high resolution. The HSPC compartment was characterized by a structured continuum of single-cell DNA methylome states. Multiple lines of evidence suggested that differentiation starts from apex HSCs possessing a lineage-naive DNA methylome state. Exit from the apex HSC state was initiated by balanced, multi-lineage DMR seeding. This early DMR programming was strictly restricted to specific DMR seeding regions, which often comprised only one or two DMCpGs. This contrasts with the conventional paradigm that functionally relevant DMRs always contain at least several DMCpGs. Further differentiation within the HSPC compartment was accompanied by continuous, gradually more lineage-specific accumulation of hypomethylation, leading to progressive DMR expansion. The dual-layer DMR/DMCpG atlas provides an essential resource for studying the epigenetic regulation of the hematopoietic differentiation process and serves as a valuable reference for the analysis of single-cell bisulfite sequencing data. This work highlights the highly-resolved, progressive, and stable nature of DNA methylome remodeling during hematopoietic differentiation and reveals several aspects of the structure and information content of the DNA methylome layer which go beyond the currently accepted paradigms. It appears likely that the DNA methylome remodeling mechanisms active in other differentiation systems and related processes, such as tumor evolution, share the same principles of hierarchical DNA methylation programming with CpG resolution. However, in many systems, the information content of the DNA methylome may be convoluted by a combination of this programming mechanism and other programming mechanisms characterized by stochastic regional accumulation of DNA methylation alterations. The analysis strategies presented in this work provide a basis for the further development of computational methods capable of dissecting the rich but complex information content of the DNA methylome with high resolution

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Measurement of the Drell-Yan Cross Section in pp Collisions at s\sqrt{s} = 7 TeV

The Drell-Yan differential cross section is measured in pp collisions at sqrt(s) = 7 TeV, from a data sample collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 36 inverse picobarns. The cross section measurement, normalized to the measured cross section in the Z region, is reported for both the dimuon and dielectron channels in the dilepton invariant mass range 15-600 GeV. The normalized cross section values are quoted both in the full phase space and within the detector acceptance. The effect of final state radiation is also identified. The results are found to agree with theoretical predictions.The Drell-Yan differential cross section is measured in pp collisions at sqrt(s) = 7 TeV, from a data sample collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 36 inverse picobarns. The cross section measurement, normalized to the measured cross section in the Z region, is reported for both the dimuon and dielectron channels in the dilepton invariant mass range 15-600 GeV. The normalized cross section values are quoted both in the full phase space and within the detector acceptance. The effect of final state radiation is also identified. The results are found to agree with theoretical predictions