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  • 1
    Publication Date: 2012-06-27
    Description: A fundamental problem in meta-analysis is how to systematically combine information from multiple statistical tests to rigorously evaluate a single overarching hypothesis. This problem occurs in systems biology when attempting to map genomic attributes to complex phenotypes such as behavior. Behavior and other complex phenotypes are influenced by intrinsic and environmental determinants that act on the transcriptome, but little is known about how these determinants interact at the molecular level. We developed an informatic technique that identifies statistically significant meta-associations between gene expression patterns and transcription factor combinations. Deploying this technique for brain transcriptome profiles from ca. 400 individual bees, we show that diverse determinants of behavior rely on shared combinations of transcription factors. These relationships were revealed only when we considered complex and variable regulatory rules, suggesting that these shared transcription factors are used in distinct ways by different determinants. This regulatory code would have been missed by traditional gene coexpression or cis-regulatory analytic methods. We expect that our meta-analysis tools will be useful for a broad array of problems in systems biology and other fields.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2014-12-17
    Description: Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing-induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity-regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359888/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whitney, Osceola -- Pfenning, Andreas R -- Howard, Jason T -- Blatti, Charles A -- Liu, Fang -- Ward, James M -- Wang, Rui -- Audet, Jean-Nicoles -- Kellis, Manolis -- Mukherjee, Sayan -- Sinha, Saurabh -- Hartemink, Alexander J -- West, Anne E -- Jarvis, Erich D -- 5T32MH018882-18/MH/NIMH NIH HHS/ -- R01 DC007218/DC/NIDCD NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01DC007218/DC/NIDCD NIH HHS/ -- R21 NS084336/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Dec 12;346(6215):1256780. doi: 10.1126/science.1256780.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Howard Hughes Medical Institute, and Duke University Medical Center, Durham, NC 27710, USA. owhitney@gmail.com apfenning@csail.mit.edu west@neuro.duke.edu jarvis@neuro.duke.edu. ; Department of Neurobiology, Howard Hughes Medical Institute, and Duke University Medical Center, Durham, NC 27710, USA. Computer Science and Artificial Intelligence Laboratory and the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. owhitney@gmail.com apfenning@csail.mit.edu west@neuro.duke.edu jarvis@neuro.duke.edu. ; Department of Neurobiology, Howard Hughes Medical Institute, and Duke University Medical Center, Durham, NC 27710, USA. ; Department of Computer Science, University of Illinois, Urbana-Champaign, IL, USA. ; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. ; Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada. ; Computer Science and Artificial Intelligence Laboratory and the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Department of Statistics, Duke University, Durham, NC, USA. ; Department of Computer Science, Duke University, Durham, NC 27708-0129, USA. ; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. owhitney@gmail.com apfenning@csail.mit.edu west@neuro.duke.edu jarvis@neuro.duke.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25504732" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Avian Proteins/chemistry/genetics/metabolism ; Brain/*physiology ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Finches/*genetics/*physiology ; *Gene Expression Regulation ; *Gene Regulatory Networks ; Genome ; Histones/metabolism ; Male ; Regulatory Sequences, Nucleic Acid ; Transcription Factors/chemistry/genetics/metabolism ; *Transcriptome ; *Vocalization, Animal
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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