29 research outputs found
Deciphering the function of obesity-associated regulatory elements within FTO
No full textGenome-wide association studies have repeatedly shown that the strongest association with obesity arises from variants in the first intron of FTO. The intronic FTO variant rs1421085 is within an adipocyte-specific enhancer and that risk allele carriers have increased IRX3 and IRX5 expression in early adipogenesis (Claussnitzer et al., 2015). Additionally, the same human risk variant was linked to decreased AKTIP, RPGRIP1L and FTO expression in iPSC-derived neurons (Stratigopoulos et al., 2016). These data point towards several likely causal transcripts and tissues at the FTO locus and essentially, several likely mechanisms. Importantly, whether any of the high-risk variants at the FTO locus has any effect on the organismal level has not been addressed so far. The aim of my DPhil project was to use novel gene manipulation strategies in vivo to mechanistically dissect the Fto regulatory circuitry in mouse to pinpoint causal transcripts their effector tissues and to unravel their physiological role in body weight regulation . Using publicly available as well as my own genomic data (ATAC-seq) revealed that the intronic FTO regulatory element in human adipocytes is conserved in mouse pre-adipocytes. Manipulation of the corresponding motif in mouse (by deleting 82 nucleotides at the mouse orthologous region around rs1421085) resulted in depot- and sex-specific alteration of target genes Irx3 and Irx5 in pre-adipocytes. In addition to recapitulating many of the human findings in mouse, my results further unravelled a new level of regulatory complexity at the FTO/Fto locus. When these mutant mice were put on a high fat diet, I found a reduction on overall fat-mass that could be linked to altered mRNA levels of Irx3 and Irx5 in pre-adipocytes. Using a number of genetic techniques, I further showed that Irx3 regulates several processes during adipocyte development, amongst which is modulation of mitochondrial function. In summary, my findings provide new insight into how variants in FTO intron 1 affect adipocyte development and more specifically how IRX3 affects early adipocyte differentiation.</p
Mouse Models of Human GWAS Hits for Obesity and Diabetes in the Post Genomic Era: Time for Reevaluation
No full textIn recent years, genome-wide association studies (GWAS) have identified hundreds of loci and thousands
of single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM)
and obesity traits [such as body mass index (BMI) and waist–hip ratio (WHR)] in the human population
(1–4). The vast majority of these SNPs are in non-coding regions of the genome and distal to
promoters, suggesting they act through gene regulation which makes their functional interpretation
challenging (5). Collectively, comparing the epigenetic landscape between mouse and human has
established new pathways involved in obesity and diabetes, and in fact, inter-species conservation
has successfully been used as criteria in finding functional and disease-relevant elements (6–8). By
contrast, genome-wide comparative analysis of the mouse and human epigenome across tissues has
highlighted the presence of cis-regulatory divergence (9, 10). New mouse engineering approaches
together with bioinformatics dissection of trait-associated regions, for example, epigenetic modifications
and genome interactions hold great promise to fully understand the underlying mechanisms
of human disease-associated non-coding variants in T2DM and obesit
The genetic underpinnings of body fat distribution
No full textIntroduction Obesity, defined as a body mass index (BMI) > 30 kilograms/meter^2 , has reached epidemic proportions: people who are overweight (BMI > 25 kg/m^2 ) or obese now comprise more than 25% of the world’s population. Obese individuals have a higher risk of comorbidity development including type 2 diabetes, cardiovascular disease, cancer, and fertility complications. Areas covered The study of monogenic and syndromic forms of obesity have revealed a small number of genes key to metabolic perturbations. Further, obesity and body shape in the general population are highly heritable phenotypes. Study of obesity at the population level, through genome-wide association studies of BMI and waist-to-hip ratio (WHR), have revealed > 150 genomic loci that associate with these traits, and highlight the role of adipose tissue and the central nervous system in obesity related traits. Studies in animal models and cell lines have helped further elucidate the potential biological mechanisms underlying obesity. In particular, these studies implicate adipogenesis and expansion of adipose tissue as key biological pathways in obesity and weight gain. Expert commentary Further work, including a focus on integrating genetic and additional genomic data types, as well as modeling obesity-like features in vitro , will be crucial in translating genome-wide association signals to the causal mechanisms driving disease
Evaluating ecosystem functions for coccolithovirus infection of Emiliania huxleyi: bridging micro, meso, and global scales
No full textThe coccolithophore Emiliania huxleyi is a globally distributed marine algal species that regularly forms large surface ocean blooms that can last from weeks to months. As a cosmopolitan species that also forms calcium carbonate plates called coccoliths, E. huxleyi plays a critical role in influencing both organic and inorganic carbon cycles. North Atlantic blooms of the algae are regularly infected by a double stranded DNA virus called Coccolithovirus (EhV). The ecological and biogeochemical influences of viral infection in marine algae are largely unknown, although studies largely suggest infection enhances chemical cycling within the microbial loop. This dissertation investigates E. huxleyi-EhV interactions within marine algal communities to further elucidate the role viruses play in influencing their host as well as the surrounding ecosystem. On a local scale, this was investigated by locating and interrogating mesoscale North Atlantic blooms of E. huxleyi with a comprehensive toolset using MODIS/AQUA satellite imagery, a suite of diagnostic lipid- and gene-based molecular biomarkers, in situ optical sensors, and sediment traps to show that EhV infections are coupled with particle aggregation, high zooplankton grazing, and enhanced downward vertical fluxes of both particulate organic and particulate inorganic carbon from the upper mixed layer to the mesopelagic. The finding that viruses can stimulate vertical carbon flux through a mechanistic interplay with zooplankton grazers introduces novel complexities into microbial ecosystem interactions. These bloom communities are further investigated using optical absorption spectra, phytoplankton pigment composition, and flow cytometry, revealing EhV infection has little influence driving the variability in phytoplankton absorption compared to community photoacclimation within the blooms. It is further observed that photoacclimation driven absorption characteristics are discernible through different phytoplankton taxonomic compositions. On the global scale, the known biogeography of EhV infection and diversity of EhVs is expanded out of the North Atlantic Ocean using a combination of the Tara Oceans global metagenome database as well as targeted regional sampling throughout the Pacific Ocean. These results reveal that EhV infection is a global phenomenon tightly coupled to E. huxleyi production and is pervasive in bloom and non-bloom environments. Collectively, these studies show that EhVs are an influential regulator of carbon cycling by enhancing biological pump efficiency and through revealing their global distribution in the ocean.Ph.D.Includes bibliographical referencesby Christien Philip Labe
Seasonal mixed layer depth shapes phytoplankton physiology, viral production, and accumulation in the North Atlantic
No full text© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Diaz, B. P., Knowles, B., Johns, C. T., Laber, C. P., Bondoc, K. G. V., Haramaty, L., Natale, F., Harvey, E. L., Kramer, S. J., Bolaños, L. M., Lowenstein, D. P., Fredricks, H. F., Graff, J., Westberry, T. K., Mojica, K. D. A., Haëntjens, N., Baetge, N., Gaube, P., Boss, E., Carlson, C. A., Behrenfeld, M. J., Van Mooy, B. A. S., Bidle, K. D. Seasonal mixed layer depth shapes phytoplankton physiology, viral production, and accumulation in the North Atlantic. Nature Communications, 12(1), (2021): 6634, https://doi.org/10.1038/s41467-021-26836-1.Seasonal shifts in phytoplankton accumulation and loss largely follow changes in mixed layer depth, but the impact of mixed layer depth on cell physiology remains unexplored. Here, we investigate the physiological state of phytoplankton populations associated with distinct bloom phases and mixing regimes in the North Atlantic. Stratification and deep mixing alter community physiology and viral production, effectively shaping accumulation rates. Communities in relatively deep, early-spring mixed layers are characterized by low levels of stress and high accumulation rates, while those in the recently shallowed mixed layers in late-spring have high levels of oxidative stress. Prolonged stratification into early autumn manifests in negative accumulation rates, along with pronounced signatures of compromised membranes, death-related protease activity, virus production, nutrient drawdown, and lipid markers indicative of nutrient stress. Positive accumulation renews during mixed layer deepening with transition into winter, concomitant with enhanced nutrient supply and lessened viral pressure.This work was made possible by NASA’s Earth Science Program in support of the North Atlantic Aerosol and Marine Ecosystem Study (15-RRNES15-0011 and 0NSSC18K1563 to K.D.B.; NNX15AF30G to M.J.B.), as well as with support from the National Science Foundation (OIA-2021032 to K.D.B., OCE-157943 to C.A.C., and OCE-1756254 to B.A.S.V.M.), the Gordon and Betty Moore Foundation (Award# 3789 to K.G.V.B.), and NASA’s Future Investigators in Space Science and Technology program (FINESST; grant #826380 to K.D.B.; graduate support to BD)
Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass
No full textBackgroundEarly benefits of Roux-en Y gastric bypass (RYGB) are partly mediated by the caloric restriction that patients undergo before and acutely after the procedure. Altered DNA methylation occurs in metabolic diseases including obesity, as well as in skeletal, muscle eight months after RYGB. The objective of this study was to test whether promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1 A), pyruvate dehydrogenase kinase isozyme-4 (PDK4), transcription factor A (TFAM), interleukin-1 beta (IL1 B), interleukin-6 (IL6) and tumor necrosis factor-α (TNF) is altered in blood after a very low calorie diet (VLCD) or RYGB.MethodsObese nondiabetic patients (n = 18, body mass index [BMI] 42.3± 4.9 kg/m2) underwent a 14-day VLCD followed by RYGB. Nonobese patients (n = 6, BMI 25.7± 2.1 kg/m2) undergoing elective cholecystectomy served as controls. DNA methylation of selected promoter regions was measured in whole blood before and after VLCD. A subgroup of seven patients was studied 1–2 days and 12± 3 months after RYGB. Promoter methylation was measured using methylated DNA capture and quantitative real-time polymerase chain reaction (PCR).ResultsVLCD decreased promoter methylation of PPARGC1 A. Methylation of PPARGC1 A, TFAM, IL1 B, IL6, and TNF promoters was changed two days after RYGB. Similar changes were also seen on day one after cholecystectomy. Moreover, methylation increased in PDK4, IL1 B, IL6, and TNF promoters 12 months after RYGB.ConclusionRYGB induced more profound epigenetic changes than VLCD in promoters of the tested genes in whole blood. Changes in DNA methylation may contribute to the improved overall metabolic health after RYGB
Premium System And Term Forming In A Construction Site Of Multi Stored Housing Area At The Abroad
No full textTez (Yüksek Lisans) -- İstanbul Teknik Üniversitesi, Fen Bilimleri Enstitüsü, 1999Thesis (M.Sc.) -- İstanbul Technical University, Institute of Science and Technology, 1999Yapılan bu tez çalışmasının amaç ve kapsamı yurtdışında komple bir şehir kurma işi olan STFA LİBYA JUFRA Projesinin 700 Ev Kaba Yapı Bölümünde görülen problemlerin tanıtılması, analiz edilmesi ve sorunlara çözüm önerileri getirilerek, işçi prodüktivitesine bağlı olarak verimliliğin arttırılması amaç sayılmıştır. Yazar, proje çalışma sisteminde etkin rol oynayan; yönetim kalitesi, iletişim, koordinasyon, çevre şartları, çalışma bölgesi koşulları, personel ihtiyaç ve problemleri gibi benzer konuları, tez çalışmasında ayrıntılı ve nedensel ilişkileriyle vermeye çalışmıştır. Çalışma sistemini oluşturmada yazar, her bir aktivite için belirli ekiplerin kurulmasını sistem yaklaşımı ve ekip oluşturma tekniğine dayanarak yapmış, daha sonra ekipler arası iletişim, standardizasyon, görev ve yetki dağılımlarını belirlemiştir. 700 Ev Kaba Yapı Grubunda performansa dayalı prim sistemi ve diğer uygulamalar yapılmıştır. İlk önce her bir aktivite için performans hedef ve standartları belirtilmiş ve buna göre denetimler yapılmıştır. Ortaya konan tüm işlerin performans düzeyleri, Burkhardt Formülü uygulamalarıyla gösterilmiştir. Performans denetimleri, ölçümler yoluyla ay sonu raporlarıyla izlenilmeye çalışılmıştır.The objective and scope of this work of thesis comprises the introduction, analysis and suggestions of solutions for the problems that have been encountered in the fabrication phase of 700 home project of STFA LIBYA JUFRA which consists of erecting a complete city at abroad and to increase the productivity depending on the laborer efficiency. The author has tried to present the problems such as; the management quality, communication, coordination, ambient conditions, the conditions of the working site, laber requirements and problems and other similar concerns which play very efficient role in the project working system in the work of thesis in the slightest details under the consideration of cause and conclusion liaisons. In the forming of working, system, the author has achieved formation of the specified teams for each activity depending on the system approach and the technique of team formation, then has determined the intercommunication, standardization, the delegation of authorities and duties of the teams accordingly. In the group of 700 home fabrication, some applications such as; premium system on the performance grounds, and other applications have been carried oft. First of all the performance target and standards are specified and the controls are implemented in accordance with such specifications. The performance levels of all the works that have been duly materialized are shown with the applications of the Burkhardt Formula. The performance controls are tried to be followed up through the month ending reports after having completed the required measurements.Yüksek LisansM.Sc
GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology
No full textThis is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Full summary statistics of the erectile dysfunction genome-wide meta-analysis are available at the following URL: http://www.geenivaramu.ee/tools/ED_AJHG_Bovijn_et_al_2018.gz and at the LD Hub GWAShare Center at the following URL: http://ldsc.broadinstitute.org/gwashare/.Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10−14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.Novo NordiskMedical Research CouncilBritish Heart Foundation Intermediate Clinical Research FellowshipLi Ka Shing FoundationWT-SSI/John Fell fundsOxfordWidenlifeNIHNational Institute for Health Research Oxford Biomedical Research Centr
