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71 Genomic regions flanking E-box binding sites influence DNA binding specificity of bHLH transcription factors through DNA shape

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Journal of Biomolecular Structure and Dynamics 2013年第SUPP 1期31卷 45-46页

作者： Raluca Gordan[a][b][*] Ning Shen[c] Iris Dror[d] Tianyin Zhou[d] John Horton[b] Remo Rohs[d] & Martha L. Bulyk[e][f] [a] Departments of Biostatistics and Bioinformatics Computer Science and Molecular Genetics and Microbiology Duke University Durham NC USA [b] Institute for Genome Sciences and Policy Duke University Durham NC 27708 USA Phone: Phone: +1 (919) 667-8673 Fax: Phone: +1 (919) 667-8673 [c] Department of Pharmacology and Cancer Biology Duke University Durham NC 27708 USA [d] Molecular and Computational Biology Program Departments of Biological Sciences Chemistry and Physics and Astronomy University of Southern California 1050 Childs Way Los Angeles CA 90089 USA [e] Division of Genetics Departments of Medicine and Pathology Brigham and Women’s Hospital and Harvard Medical School Boston MA 02115 USA [f] Harvard-MIT Division of Health Sciences and Technology (HST) Harvard Medical School Boston MA 02115 USA

Transcriptional regulation of gene expression is enacted mainly through binding of transcription factors (TFs) to specific, short DNA sites in cis-regulatory regions of genes. Most TFs are members of protein families that share a common DNA-binding domain and thus recognize similar DNA-binding sequences. It is not well understood why paralogous TFs often bind different genomic target sitesin vivoto effect different regulatory programs, despite apparently recognizing the same sequence motifs. Here, we designed custom protein-binding microarrays (PBMs) to analyze the DNA-binding specificities of twoSaccharomyces cerevisiaebasic helix-loop-helix (bHLH) proteins, Tye7 and Cbf1, as a model system. Our data reveal that E-box DNA-binding sequences (CAnnTG), when tested in the context of their native genomic flanking sequences, are bound differently by Cbf1 and Tye7. Computational models of the PBM data indicate that DNA sequence features located in the genomic sequences outside the E-box contribute to DNA-binding specificityin vitro. Our analyses suggest that these flanking regions affect DNA-binding specificity indirectly by influencing the three-dimensional structure of the E-box binding sites. Finally, we show that these subtle differences in intrinsic sequence preferences of Cbf1 and Tye7in vitrohelp to explain their differential DNA-binding preferencesin vivo. Our results provide further evidence that the local shape of DNA-binding sites may be an important feature in distinguishing the DNA-binding preferences among paralogous TFs and thus may play a widespread role in determining how transcriptional regulatory specificity within TF families is achieved.

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Research highlights

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Lab on a Chip 2013年第10期13卷 1842-1845页

作者： João Ribas Mark W. Tibbitt Mehmet R. Dokmeci Ali Khademhosseini Center for Biomedical Engineering Department of Medicine Brigham and Women's Hospital Harvard Medical School Cambridge Massachusetts 02139 USA Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA PhD Program in Experimental Biology and Biomedicine CNC-Center for Neuroscience and Cell Biology and Institute for Interdisciplinary Research (IIIUC) University of Coimbra 3004-517 Coimbra Portugal Biocant–Center of Innovation and Biotechnology 3060-197 Cantanhede Portugal Department of Chemical and Biological Engineering University of Colorado Boulder Colorado 80303 USA Wyss Institute for Biologically Inspired Engineering Harvard University Boston Massachusetts 02115 USA World Premier International–Advanced Institute for Materials Research (WPI-AIMR) Tohoku University Sendai 980-8577 Japan

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Lab on a Chip 2013年第4期13卷 599-601页

作者： Francesco Piraino João Ribas Mehmet R. Dokmeci Ali Khademhosseini Bioengineering Department Politecnico di Milano Piazza Leonardo da Vinci 32 20133 Milano Italy Center for Biomedical Engineering Department of Medicine Brigham and Women's Hospital Harvard Medical School Cambridge Massachusetts 02139 USA Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Biocant-Center of Innovation and Biotechnology 3060-197 Cantanhede Portugal PhD Program in Experimental Biology and Biomedicine CNC-Centre for Neuroscience and Cell Biology 3004-517 Coimbra Portugal Wyss Institute for Biologically Inspired Engineering Harvard University Boston Massachusetts 02115 USA World Premier International – Advanced Institute for Materials Research (WPI-AIMR) Tohoku University Sendai 980-8577 Japan

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Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information (vol 91, pg 626, 2022)

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BIOLOGICAL PSYCHIATRY 2022年第7期91卷 690-690页

作者： Maihofer, Adam X. Vinkers, Christiaan H. Department of Psychiatry University of California San Diego La Jolla California Department of Family Medicine and Public Health University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California. Electronic address: amaihofer@health.ucsd.edu. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Psychiatry Massachusetts General Hospital Boston Massachusetts. Social Genetic and Developmental Psychiatry Centre Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom National Institute of Health Research Maudsley Biomedical Research Centre King's College London London United Kingdom. Department of Psychiatry Harvard Medical School Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts Center of Excellence in Depression and Anxiety Disorders Belmont Massachusetts. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts. Department of Psychiatry University of California San Diego La Jolla California Center of Excellence for Stress and Mental Health Veterans Affairs Healthcare System San Diego California Research Service Veterans Affairs Healthcare System San Diego California. Duke Molecular Physiology Institute Duke University School of Medicine Durham North Carolina. Department of Psychiatry Veterans Affairs Connecticut Healthcare System West Haven Connecticut Department of Psychiatry Yale University School of Medicine New Haven Connecticut. Department of Epidemiology Harvard T.H. Chan School of Public Health Boston Massachusetts Department of Epidemiology Columbia University Mailman School of Public Health New York. Division of Mental Health Atlanta Veterans Affairs Medical Center

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

关键词： GWAS Genetics Heritability PTSD PheWAS Trauma

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Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study (vol 113, pg 1490, 2021)

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AMERICAN JOURNAL OF CLINICAL NUTRITION 2021年第6期113卷 1715-1715页

作者： Tsilidis, K. K. Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon France Department of Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom Medical Research Council Integrative Epidemiology Unit Department of Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom University Hospitals Bristol National Health Service Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre University of Bristol Bristol United Kingdom Medical Research Council Biostatistics Unit School of Clinical Medicine University of Cambridge Cambridge United Kingdom Department of Preventive Medicine and Community Health The University of Texas Medical Branch Galveston TX USA Nuffield Department of Population Health University of Oxford Oxford United Kingdom Division of Human Nutrition and Health Wageningen University & Research Wageningen Netherlands Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Bethesda MD USA Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ) Heidelberg Germany Medical Genetics Service University Hospital Center (CHU) Nantes Nantes France Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom Huntsman Cancer Institute University of Utah Salt Lake City UT USA Department of Population Health Sciences University of Utah Salt Lake City UT USA Division of Preventive Oncology German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg Germany German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg Germany Institute for Health Research Kaiser Permanente Colorado Denver CO USA Be

Background The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also *** To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).Methods Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR *** Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, c

关键词： Mendelian randomization genes nutrition supplements colorectal cancer

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SERS-coded cold nanorods as a multifunctional platform for densely multiplexed near-infrared imaging and photothermal heating

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Advanced Materials 2009年第31期21卷 3175-3180页

作者： Von Maltzahn, Geoffrey Centrone, Andrea Park, Ji-Ho Ramanathan, Renuka Sailor, Michael J. Alan Hatton, T. Bhatia, Sangeeta N. Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 United States David H. Koch Institute for Integrative Cancer Research Department of Medicine Brigham and Women's Hospital Boston MA United States Department of Chemical Engineering Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 United States Materials Science and Engineering Program Department of Chemistry and Biochemistry University of California San Diego 9500 Gilman San DiegoCA 92093 United States Departments of Bioengineering and Nanoengineering University of California San Diego 9500 Cilman San Diego CA 92093 United States

The use of near-infrared plasmon resonance of gold nanorods (NR) to offer an integrated platform for multiplexed Raman detection and remote-controlled photothermal heating is analyzed. Surface enhanced Raman scattering (SERS)-coded NRs were efficiently detected following subcutaneous or intratumoral injection and enabled remote photothermal tumor heating to ablative temperatures. Cetyltrimethylammonium bromide (CTAB)-coated gold NRs were bought from Nanopartz with a peak plasmon resonance at 790 nm. NRs were purified further with multiple rounds of centrifugation using molecular weight cutoff centrifugal filters and stored at 200 pm at 4C. The SERS intensities of NRs coated with different dyes were compared using ethanol as an internal standard. The best NRs were selected by comparing the peak height ratio of the dye's most intense SERS peak to the peak height of the ethanol vibration at 879 cm-1 used as an internal standard.

关键词： Ethanol

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Highly accelerated EPI with wave encoding and multi-shot simultaneous multi-slice imaging

arXiv

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arXiv 2021年

作者： Cho, Jaejin Liao, Congyu Tian, Qiyuan Zhang, Zijing Xu, Jinmin Lo, Wei-Ching Poser, Benedikt A. Stenger, V. Andrew Stockmann, Jason Setsompop, Kawin Bilgic, Berkin Athinoula A. Martinos Center for Biomedical Imaging Massachusetts General Hospital BostonMA United States Harvard Medical School BostonMA United States Radiological Sciences Laboratory Stanford University Palo AltoCA United States State Key Laboratory of Modern Optical Instrumentation College of Optical Science and Engineering Zhejiang University Hangzhou China Siemens Medical Solutions BostonMA United States Maastricht Brain Imaging Centre Maastricht University Maastricht Netherlands MR Research Program Department of Medicine John A. Burns School of Medicine University of Hawai'i HI United States Harvard-MIT Health Sciences and Technology Massachusetts Institute of Technology CambridgeMA United States

Purpose: To introduce wave encoded acquisition and reconstruction techniques for highly accelerated echo planar imaging (EPI) with reduced g-factor penalty and image artifacts. Method: Wave-EPI involves playing sinusoidal gradients during the EPI readout while employing interslice shifts as in blipped-CAIPI acquisitions. This spreads the aliasing in all spatial directions, thereby taking better advantage of 3D coil sensitivity profiles. The amount of voxel spreading that can be achieved by the wave gradients during the short EPI readout period is constrained by the slew rate of the gradient coils and peripheral nerve stimulation (PNS) monitor. We propose to use a "half-cycle" sinusoidal gradient to increase the amount of voxel spreading that can be achieved while respecting the slew and stimulation constraints. Extending wave-EPI to multi-shot acquisition minimizes geometric distortion and voxel blurring at high in-plane resolution, while structured low-rank regularization mitigates shot-to-shot phase variations without additional navigators. We propose to use different point spread functions (PSFs) for the k-space lines with positive and negative polarities, which are calibrated with a FLEET-based reference scan and allow for addressing gradient imperfections. Results: Wave-EPI provided whole-brain single-shot gradient echo (GE) and multi-shot spin echo (SE) EPI acquisitions at high acceleration factors and was combined with g-Slider slab encoding to boost the SNR level in 1mm isotropic diffusion imaging. Relative to blipped-CAIPI, wave-EPI reduced average and maximum g-factors by up to 1.21- and 1.37-fold, respectively. Conclusion: Wave-EPI allows highly accelerated single- and multi-shot EPI with reduced g-factor and artifacts and may facilitate clinical and neuroscientific applications of EPI by improving the spatial and temporal resolution in functional and diffusion imaging. Copyright © 2021, The Authors. All rights reserved.

关键词： Signal encoding

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Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants

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Science (New York, N.Y.) 2025年第6734期387卷 eadp4753页

作者： Liu, Hongbo Abedini, Amin Ha, Eunji Ma, Ziyuan Sheng, Xin Dumoulin, Bernhard Qiu, Chengxiang Aranyi, Tamas Li, Shen Dittrich, Nicole Chen, Hua-Chang Tao, Ran Tarng, Der-Cherng Hsieh, Feng-Jen Chen, Shih-Ann Yang, Shun-Fa Lee, Mei-Yueh Kwok, Pui-Yan Wu, Jer-Yuarn Chen, Chien-Hsiun Khan, Atlas Limdi, Nita A. Wei, Wei-Qi Walunas, Theresa L. Karlson, Elizabeth W. Kenny, Eimear E. Luo, Yuan Kottyan, Leah Connolly, John J. Jarvik, Gail P. Weng, Chunhua Shang, Ning Cole, Joanne B. Mercader, Josep M. Mandla, Ravi Majarian, Timothy D. Florez, Jose C. Haas, Mary E. Lotta, Luca A. Drivas, Theodore G. Vy, Ha My T Nadkarni, Girish N. Wiley, Laura K. Wilson, Melissa P. Gignoux, Christopher R. Rasheed, Humaira Thomas, Laurent F. Åsvold, Bjørn Olav Brumpton, Ben M. Hallan, Stein I. Hveem, Kristian Zheng, Jie Hellwege, Jacklyn N. Zawistowski, Matthew Zöllner, Sebastian Franceschini, Nora Hu, Hailong Zhou, Jianfu Kiryluk, Krzysztof Ritchie, Marylyn D. Palmer, Matthew Edwards, Todd L. Voight, Benjamin F. Hung, Adriana M. Susztak, Katalin Department of Medicine Renal Electrolyte and Hypertension Division University of Pennsylvania Philadelphia PA United States Institute of Diabetes Obesity and Metabolism University of Pennsylvania Philadelphia PA United States Department of Genetics University of Pennsylvania Philadelphia PA United States Penn-CHOP Kidney Innovation Center University of Pennsylvania Philadelphia PA United States Liangzhu Laboratory Zhejiang University 1369 West Wenyi Road Hangzhou Zhejiang China Department of Nephrology Children' Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang China Institute of Molecular Life Sciences HUN-REN Research Center for Natural Sciences Budapest Hungary Department of Molecular Biology Semmelweis University Budapest Hungary Department of Medicine Federal University of São Paulo São Paulo Brazil Department of Biostatistics Vanderbilt University Medical Center Nashville TN United States Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN United States Institute of Clinical Medicine School of Medicine National Yang Ming Chiao Tung University ROC Taipei Taiwan Division of Nephrology Department of Medicine Taipei Veterans General Hospital ROC Taipei Taiwan Institute of Biomedical Sciences Academia Sinica ROC Taipei Taiwan Cardiovascular Center Taichung Veterans General Hospital Taichung Taiwan ROC National Chung Hsing University Taichung Taiwan ROC Heart Rhythm Center Division of Cardiology Department of Medicine Taipei Veterans General Hospital ROC Taipei Taiwan Department of Internal Medicine College of Medicine National Yang Ming Chiao Tung University ROC Taipei Taiwan Institute of Medicine Chung Shan Medical University Taichung Taiwan ROC Department of Medical Research Chung Shan Medical University Hospital Taichung Taiwan ROC Division of Endocrinology and Metabolism Department of Internal Medicine Kaohsiung Medical Universit

Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on allele-specific gene expression and regulatory circuitries in more than 700 human kidneys and 237,000 cells. We found 1363 coding variants disrupting 782 genes, with 601 genes also targeted by regulatory variants and convergence in 161 genes. Integrating 32 types of genetic information, we present the "Kidney Disease Genetic Scorecard" for prioritizing potentially causal genes, cell types, and druggable targets for kidney disease.

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REDUCING INTER-OBSERVER VARIABILITY IN ENDOMYOCARDIAL BIOPSY ASSESSMENT

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Journal of Pathology Informatics 2022年 13卷 100058-100058页

作者： Lipkova, Jana Chen, Tiffany Y. Lu, Ming Y. Chen, Richard J. Shady, Maha Williams, Mane Wang, Jingwen Noor, Zahra mitchell, Richard N. Mahmood, Faisal Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA Broad Institute of Harvard and MIT Cambridge MA USA Data Science Program Dana-Farber Cancer Institute Boston MA USA Harvard-MIT Health Sciences and Technology Cambridge MA USA Department of Biomedical Informatics Harvard Medical School Boston MA USA

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Cochlear tuning… of mice and men

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AIP Conference Proceedings 2018年第1期1965卷

作者： Shirin Farrahi Roozbeh Ghaffari Jonathan B. Sellon Hideko H. Nakajima Dennis M. Freeman 1Research Laboratory of Electronics MIT Cambridge Massachusetts USA 2Department of Electrical Engineering and Computer Science MIT Cambridge Massachusetts USA 3Harvard-MIT Program in Health Sciences and Technology Cambridge Massachusetts USA 4Department of Otolaryngology Harvard Medical School and Massachusetts Eye and Ear Boston Massachusetts USA

It has been suggested that humans discriminate different frequency sounds with greater selectivity than other mammals. However, mechanisms that could underlie higher frequency selectivity in humans are unclear. Recent studies show that the tectorial membrane (TM) supports longitudinally propagating waves, and the spread of excitation of these TM waves has been implicated in controlling the tuning properties in a mutant mouse model of hearing. Here we compare TM morphology and waves in humans and mice and show that despite some differences in morphology, the spread of excitation of TM waves is similar in spatial extent. However, the cochlear maps of humans and mice differ significantly, with similar cochlear distances mapping to a narrower range of best frequencies in humans than in mice. By coupling different frequency ranges, TM waves could contribute to differences in frequency tuning in mammals, with the smaller human range of frequencies corresponding to sharper frequency tuning.

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