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      Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals

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          Summary

          To mechanistically characterize the microevolutionary processes active in altering transcription factor (TF) binding among closely related mammals, we compared the genome-wide binding of three tissue-specific TFs that control liver gene expression in six rodents. Despite an overall fast turnover of TF binding locations between species, we identified thousands of TF regions of highly constrained TF binding intensity. Although individual mutations in bound sequence motifs can influence TF binding, most binding differences occur in the absence of nearby sequence variations. Instead, combinatorial binding was found to be significant for genetic and evolutionary stability; cobound TFs tend to disappear in concert and were sensitive to genetic knockout of partner TFs. The large, qualitative differences in genomic regions bound between closely related mammals, when contrasted with the smaller, quantitative TF binding differences among Drosophila species, illustrate how genome structure and population genetics together shape regulatory evolution.

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          Highlights

          • Earliest steps of regulatory evolution in mammals captured using five mouse species

          • Interspecies differences in TF binding are rarely caused by DNA variation in motifs

          • Cobound TFs change their genomic binding cooperatively in closely related mammals

          • Genetic knockouts revealed the extent of cooperative stabilization in TF binding clusters

          Abstract

          Microevolutionary mechanisms create different transcription factor binding patterns between mammals, shedding light on the regulatory mechanisms partially underlying speciation.

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          Most cited references 40

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          Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures.

          Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spurious and incorrect gene annotations, and numerous unusual gene structures, including abundant stop-codon readthrough. Similarly, we predict non-protein-coding RNA genes and structures, and new microRNA (miRNA) genes. We provide evidence of miRNA processing and functionality from both hairpin arms and both DNA strands. We identify several classes of pre- and post-transcriptional regulatory motifs, and predict individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies.
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            Variation in transcription factor binding among humans.

            Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. The binding sites of RNA polymerase II (PolII) and a key regulator of immune responses, nuclear factor kappaB (p65), were mapped in 10 lymphoblastoid cell lines, and 25 and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with single-nucleotide polymorphisms and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between humans and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding, and they provide insight into the genetic events responsible for these differences.
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              Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.

              The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1alpha [HNF1alpha], -1beta, -3alpha, -3beta, -3gamma, -4alpha, and -6 and members of the c/ebp family). Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1alpha-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4alpha-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4alpha is indispensable for hepatocyte differentiation. However, the function of HNF4alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.
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                Author and article information

                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                01 August 2013
                01 August 2013
                : 154
                : 3
                : 530-540
                Affiliations
                [1 ]Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK
                [2 ]European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK
                [3 ]Genetics & Genome Biology Program, Hospital for Sick Children (SickKids) and Department of Molecular Genetics, University of Toronto, 101 College Street, East Tower, Toronto, ON M5G 1L7, Canada
                [4 ]Department of Genetics, University of Cambridge, Cambridge CB1 3QA, UK
                [5 ]Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1QR, UK
                [6 ]Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece
                [7 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
                Author notes
                []Corresponding author flicek@ 123456ebi.ac.uk
                [∗∗ ]Corresponding author duncan.odom@ 123456cruk.cam.ac.uk
                [8]

                These authors contributed equally to this work and are listed alphabetically

                Article
                CELL7008
                10.1016/j.cell.2013.07.007
                3732390
                23911320
                © 2013 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                Categories
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                Cell biology

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