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      Inflammation-induced repression of Foxp3-bound chromatin in regulatory T cells

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          Abstract

          The transcription factor Foxp3 is indispensable for the ability of regulatory T (Treg) cells to suppress fatal inflammation. Here, we characterized the role of Foxp3 in chromatin remodeling and regulation of gene expression in actively suppressing Treg cells in an inflammatory setting. Although genome-wide Foxp3 occupancy of DNA regulatory elements was similar in resting and in vivo activated Treg cells, Foxp3-bound enhancers were poised for repression only in activated Treg cells. Following activation, Foxp3-bound sites showed reduced chromatin accessibility and selective H3K27 tri-methylation, which was associated with Ezh2 recruitment and downregulation of nearby gene expression. Thus, Foxp3 poises its targets for repression by facilitating formation of repressive chromatin in regulatory T cells upon their activation in response to inflammatory cues.

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          A unique chromatin signature uncovers early developmental enhancers in humans.

          Alvaro Rada-Iglesias, Ruchi Bajpai, Tomek Swigut … (2011)
          Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
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            Design and analysis of ChIP-seq experiments for DNA-binding proteins

            Peter V. Kharchenko, Michael Tolstorukov, Peter Park (2008)
            Recent progress in massively parallel sequencing platforms has allowed for genome-wide measurements of DNA-associated proteins using a combination of chromatin immunoprecipitation and sequencing (ChIP-seq). While a variety of methods exist for analysis of the established microarray alternative (ChIP-chip), few approaches have been described for processing ChIP-seq data. To fill this gap, we propose an analysis pipeline specifically designed to detect protein binding positions with high accuracy. Using three separate datasets, we illustrate new methods for improving tag alignment and correcting for background signals. We also compare sensitivity and spatial precision of several novel and previously described binding detection algorithms. Finally, we analyze the relationship between the depth of sequencing and characteristics of the detected binding positions, and provide a method for estimating the sequencing depth necessary for a desired coverage of protein binding sites.
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              Moderated statistical tests for assessing differences in tag abundance.

              Mark Robinson, Gordon K. Smyth (2007)
              Digital gene expression (DGE) technologies measure gene expression by counting sequence tags. They are sensitive technologies for measuring gene expression on a genomic scale, without the need for prior knowledge of the genome sequence. As the cost of sequencing DNA decreases, the number of DGE datasets is expected to grow dramatically. Various tests of differential expression have been proposed for replicated DGE data using binomial, Poisson, negative binomial or pseudo-likelihood (PL) models for the counts, but none of the these are usable when the number of replicates is very small. We develop tests using the negative binomial distribution to model overdispersion relative to the Poisson, and use conditional weighted likelihood to moderate the level of overdispersion across genes. Not only is our strategy applicable even with the smallest number of libraries, but it also proves to be more powerful than previous strategies when more libraries are available. The methodology is equally applicable to other counting technologies, such as proteomic spectral counts. An R package can be accessed from http://bioinf.wehi.edu.au/resources/
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Journal ID (iso-abbrev): Nat. Immunol.
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 24 April 2014
                Publication date (Electronic): 13 April 2014
                Publication date (Print): June 2014
                Publication date PMC-release: 01 December 2014
                Volume: 15
                Issue: 6
                Pages: 580-587
                Affiliations
                [1 ] Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
                [2 ] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
                [3 ]Ludwig Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
                [4 ] Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA
                Author notes
                Correspondence should be addressed to A.Y.R. ( rudenska@ 123456mskcc.org ).
                Article
                Manuscript ID: NIHMS574501
                DOI: 10.1038/ni.2868
                PMC ID: 4112080
                PubMed ID: 24728351
                SO-VID: bd2a5bac-2e86-44ac-9c8d-d83ec7c16900
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                ScienceOpen disciplines: Immunology
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                ScienceOpen disciplines: Immunology

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