Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in <i>Cebpa null</i> Progenitors

Transcription factors PU.1 and CEBPA are required for the proper coordination of enhancer activity during granulocytic-monocytic (GM) lineage differentiation to form myeloid cells. However, precisely how these factors control the chronology of enhancer establishment during differentiation is not known. Through integrated analyses of enhancer dynamics, transcription factor binding, and proximal gene expression during successive stages of murine GM-lineage differentiation, we unravel the distinct kinetics by which PU.1 and CEBPA coordinate GM enhancer activity. We find no evidence of a pioneering function of PU.1 during late GM-lineage differentiation. Instead, we delineate a set of enhancers that gain accessibility in a CEBPA-dependent manner, suggesting a pioneering function of CEBPA. Analyses of Cebpa null bone marrow demonstrate that CEBPA controls PU.1 levels and, unexpectedly, that the loss of CEBPA results in an early differentiation block. Taken together, our data provide insights into how PU.1 and CEBPA functionally interact to drive GM-lineage differentiation

Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human mutant AML and the corresponding mouse model, we identified , encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Atmosphere-ocean-ice interactions in the Amundsen Sea Embayment, West Antarctica

Over recent decades outlet glaciers of the Amundsen Sea Embayment (ASE), West Antarctica, have accelerated, thinned and retreated, and are now contributing approximately 10% to global sea level rise. All the ASE glaciers flow into ice shelves, and it is the thinning of these since the 1970s, and their ungrounding from “pinning points” that is widely held to be responsible for triggering the glaciers’ decline. These changes have been linked to the inflow of warm Circumpolar Deep Water (CDW) onto the ASE's continental shelf. CDW delivery is highly variable, and is closely related to the regional atmospheric circulation. The ASE is south of the Amundsen Sea Low (ASL), which has a large variability and which has deepened in recent decades. The ASL is influenced by the phase of the Southern Annular Mode, along with tropical climate variability. It is not currently possible to simulate such complex atmosphere-ocean-ice interactions in models, hampering prediction of future change. The current retreat could mark the beginning of an unstable phase of the ASE glaciers that, if continued, will result in collapse of the West Antarctic Ice Sheet, but numerical ice-sheet models currently lack the predictive power to answer this question. It is equally possible that the recent retreat will be short-lived and that the ASE will find a new stable state. Progress is hindered by incomplete knowledge of bed topography in the vicinity of the grounding line. Furthermore, a number of key processes are still missing or poorly represented in models of ice-flow

Sheep in the Vineyard: First Insights into a New Integrated Crop–Livestock System in Central Europe

The multiple land use of agricultural areas is a building block for increased land use efficiency. Unlike monoculture, integrated crop–livestock systems optimally improve ecosystem services, making it an important field of research and application for adapting land use and food systems that have sustainability deficits. The integration of sheep in viticulture production is described as a promising example of an integrated crop–livestock system. While some studies of the integration of sheep into vineyards are already available for other parts of the world, there is still no research on its implementation in Central European viticulture systems. In order to fill this gap of knowledge, we conducted standardized interviews with 34 winegrowers who already graze sheep in their vineyards. The method allowed a wider overview of the implementation of the integrated crop-livestock system than would have been possible with other approaches. Furthermore, the authors kept sheep in their own vineyard for three years to evaluate the statements of the survey participants. The period during which sheep graze in vineyards is quite heterogeneous in Central Europe. Some farms use sheep only during vine dormancy; others also let sheep graze during a certain period in summer. There are also viticulture training systems where grazing is almost continuously possible. In Central Europe, summer grazing normally requires operational adjustments such as lifting the wires of the training system and branches of the vine; otherwise, the vines could be damaged. This option seems to be tailored to the training system in use. Some interviewees mentioned that sheep not only use the accompanying vegetation as fodder and therefore control the undervine growth, but in some cases, they were also able to replace other work processes, such as defoliating the grape zone or cleaning undesired vine shoots near the ground. However, a high additional workload due to livestock keeping was also mentioned by some survey participants. Some of the interviewees cooperate with shepherds, which could help to solve this challenge. Finally, we summarize possible opportunities and risks of this integrated crop–livestock system. Integrating sheep in vineyards seems to be quite feasible in the period of vine dormancy, whereas more information and considerably more effort is needed to integrate sheep during the vegetation period. Further research is needed to answer open questions especially for the necessary adaptions of the common vine training system or the implementation of alternative systems more suitable to combine with livestock keeping. Some practitioners found opportunities to merchandize the use of sheep in wine sales. This potentially unique selling point could be a solution for a broader consideration of sheep in vineyards

Dairies in Germany: Key Factors for Grassland Conservation?

Germany is the largest milk producer of the 28 EU Member States (statistically still including Great Britain) and dairying is the most important single sector in German agriculture. Dairies are of central importance in the value chain, but very little is known about their objectives and perspectives in relation to grassland management, feedstuffs deriving from grassland and towards resource conservation issues. This study gives an insight on the way German dairies think about and act in such topics by using a standardized survey method. The survey revealed little to no linkage between the size of dairies and their interest in conservation issues on grassland and very little consideration of extensive grasslands. Dairies are divided over questions of governance for a more sustainable milk market and on the nature of their relationships with farmers. There is evidence that the German dairy industry is willing to contribute to a more sustainable and more robust milk market, but the enterprises mostly regard other market actors as more important. According to this survey, consumers will tend to opt for more sustainable milk products in future and there are possibilities to raise the willingness to pay

Sheep in the Vineyard: Suitability of Different Breeds and Potential Breeding Objectives

Protecting a breed of sheep is simple when there is demand for its breed traits, but new market options are often hard to find. In general, grazing sheep are able to take over some viticultural work. Here, we address a new and promising integrated crop-livestock system that involves the integration of sheep in the vineyard during the growing season. Using sheep in a vineyard entails opportunities but also risks, such as the current lack of information, specifically in relation to breed traits. In our survey, we evaluated 26 breeds for their suitability for grazing as long as possible in Central European vineyards during the growing season. First, the breed traits required were identified. Then, 94 flock book breeders were interviewed about specific breed traits. The height of a sheep’s muzzle is particularly important for assessing the suitability of a breed, as it defines the potential impact on the foliage area during the growing season. To determine the height of the muzzle, 179 flock book animals were measured. We found that the most important breeding objective for a new breed of sheep is the inability to stand on two legs. Adult animals of the breed Shropshire, and among these especially the shorter-legged Danish type, and Southdown, show a widespread inability to stand on two legs. Ouessant sheep are able to do so, yet are suitable with some limitations. Due to their extraordinarily small size, their reach is limited, as is their grazing performance. Thus, three of the 26 breeds studied here seem suitable for use in the most widespread vine training systems of Central Europe during the growing season. Targeted breeding could further improve the suitability of sheep for viticulture. Our findings could help to protect breeds and breed traits