ALBERT

Description: Parent-of-origin-specific expression at imprinted genes is regulated by allele-specific DNA methylation at imprinting control regions (ICRs). This mechanism of gene regulation, where one element controls allelic expression of multiple genes, is not fully understood. Furthermore, the mechanism of gene dysregulation through ICR epimutations, such as loss or gain of DNA methylation, remains a mystery. We have used genetic mouse models to dissect ICR-mediated genetic and epigenetic regulation of imprinted gene expression. The H19/insulin-like growth factor 2 (Igf2) ICR has a multifunctional role including insulation, activation and repression. Microdeletions at the human H19/IGF2 ICR (IC1) are proposed to be responsible for IC1 epimutations associated with imprinting disorders such as Beckwith–Wiedemann syndrome (BWS). Here, we have generated and characterized a mouse model that mimics BWS microdeletions to define the role of the deleted sequence in establishing and maintaining epigenetic marks and imprinted expression at the H19/IGF2 locus. These mice carry a 1.3 kb deletion at the H19/Igf2 ICR [2,3] removing two of four CCCTC-binding factor (CTCF) sites and the intervening sequence, ~75% of the ICR. Surprisingly, the 2,3 deletion does not perturb DNA methylation at the ICR; however, it does disrupt imprinted expression. While repressive functions of the ICR are compromised by the deletion regardless of tissue type, insulator function is only disrupted in tissues of mesodermal origin where a significant amount of CTCF is poly(ADP-ribosyl)ated. These findings suggest that insulator activity of the H19/Igf2 ICR varies by cell type and may depend on cell-specific enhancers as well as posttranslational modifications of the insulator protein CTCF.

Description: : ART is a set of simulation tools that generate synthetic next-generation sequencing reads. This functionality is essential for testing and benchmarking tools for next-generation sequencing data analysis including read alignment, de novo assembly and genetic variation discovery. ART generates simulated sequencing reads by emulating the sequencing process with built-in, technology-specific read error models and base quality value profiles parameterized empirically in large sequencing datasets. We currently support all three major commercial next-generation sequencing platforms: Roche's 454, Illumina's Solexa and Applied Biosystems' SOLiD. ART also allows the flexibility to use customized read error model parameters and quality profiles. Availability: Both source and binary software packages are available at http://www.niehs.nih.gov/research/resources/software/art Contact: weichun.huang@nih.gov ; gabor.marth@bc.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Duchenne muscular dystrophy (DMD) is caused by a lack of the dystrophin protein and has no effective treatment at present. Zebrafish provide a powerful in vivo tool for high-throughput therapeutic drug screening for the improvement of muscle phenotypes caused by dystrophin deficiency. Using the dystrophin-deficient zebrafish, sapje , we have screened a total of 2640 compounds with known modes of action from three drug libraries to identify modulators of the disease progression. Six compounds that target heme oxygenase signaling were found to rescue the abnormal muscle phenotype in sapje and sapje -like, while upregulating the inducible heme oxygenase 1 (Hmox1) at the protein level. Direct Hmox1 overexpression by injection of zebrafish Hmox1 mRNA into fertilized eggs was found to be sufficient for a dystrophin-independent restoration of normal muscle via an upregulation of cGMP levels. In addition, treatment of mdx 5cv mice with the PDE5 inhibitor, sildenafil, which was one of the six drugs impacting the Hmox1 pathway in zebrafish, significantly increased the expression of Hmox1 protein, thus making Hmox1 a novel target for the improvement of dystrophic symptoms. These results demonstrate the translational relevance of our zebrafish model to mammalian models and support the use of zebrafish to screen for new drugs to treat human DMD. The discovery of a small molecule and a specific therapeutic pathway that might mitigate DMD disease progression could lead to significant clinical implications.

Description: Rivers are essential to aquatic ecosystem and societal sustainability, but are increasingly impacted by water withdrawals, land use change, and climate change. The relative and cumulative effects of these stressors on continental river flows are relatively unknown. In this study, we used an integrated water balance and flow routing model to evaluate the impacts of 2010 impervious cover and water withdrawal on river flow across the Conterminous US at the 8-digit Hydrologic Unit Code (HUC) watershed scale. We then estimated the impacts of projected change in withdrawals, impervious cover, and climate under the B1 "low" and A2 "high" emission scenarios on river flows by 2060. Our results suggest that compared to no impervious cover, 2010 levels of impervious cover increased river flows by 9.9% on average with larger impacts in and downstream of major metropolitan areas. In contrast, compared to no water withdrawals, 2010 withdrawals decreased river flows by 1.4% on average with larger impacts in heavily irrigated arid regions of Western US. By 2060, impacts of climate change were predicted to overwhelm the potential gain in river flow due to future changes in impervious cover and add to the potential reduction in river flows from withdrawals, decreasing mean annual river flows from 2010 levels by 16% on average. However, increases in impervious cover by 2060 may offset the impact of climate change during the growing season in some watersheds. Large water withdrawals will aggravate the predicted impact of climate change on river flows, particularly in the Western US. Given that the impacts of land use, withdrawals and climate may be either additive or offsetting in different magnitudes, integrated and spatially explicit modelling and management approaches are necessary to effectively manage water resources for aquatic life and human use in the face of global change.

Description: Rivers are essential to aquatic ecosystem and societal sustainability, but are increasingly impacted by water withdrawals, land-use change, and climate change. The relative and cumulative effects of these stressors on continental river flows are relatively unknown. In this study, we used an integrated water balance and flow routing model to evaluate the impacts of impervious cover and water withdrawal on river flow across the conterminous US at the 8-digit Hydrologic Unit Code (HUC) watershed scale. We then estimated the impacts of projected change in withdrawals, impervious cover, and climate under the B1 "Low" and A2 "High" emission scenarios on river flows by 2060. Our results suggest that compared to no impervious cover, 2010 levels of impervious cover increased river flows by 9.9% on average with larger impacts in and downstream of major metropolitan areas. In contrast, compared to no water withdrawals, 2005 withdrawals decreased river flows by 1.4% on average with larger impacts in heavily irrigated arid regions of Western US. By 2060, impacts of climate change were predicted to overwhelm the potential gain in river flow due to future changes in impervious cover and add to the potential reduction in river flows from withdrawals, decreasing mean annual river flows from 2010 levels by 16% on average. However, increases in impervious cover by 2060 may offset the impact of climate change during the growing season in some watersheds. Large water withdrawals will aggravate the predicted impact of climate change on river flows, particularly in the Western US. Predicted ecohydrological impacts of land cover, water withdrawal, and climate change will likely include alteration of the terrestrial water balance, stream channel habitat, riparian and aquatic community structure in snow-dominated basins, and fish and mussel extirpations in heavily impacted watersheds. These changes may also require new infrastructure to support increasing anthropogenic demand for water, relocation of agricultural production, and/or water conservation measures. Given that the impacts of land use, withdrawals and climate may be either additive or offsetting in different magnitudes, integrated and spatially explicit modeling and management approaches are necessary to effectively manage water resources for aquatic life and human use in the face of global change.