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      Heterochromatin-associated interactions of Drosophila HP1a with dADD1, HIPP1, and repetitive RNAs

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          Abstract

          Heterochromatin protein 1 (HP1a) plays conserved roles in gene silencing and heterochromatin and is also implicated in transcription, DNA replication, and repair. Using BioTAP-XL mass spectrometry and sequencing across multiple life stages of Drosophila, Alekseyenko et al. identify HP1a chromatin-associated protein and RNA interactions. They discover 13 novel candidates among the top interactions. Furthermore, HP1a selectively associates with a broad set of RNAs transcribed from repetitive regions. The validation of several novel HP1a protein interactors reveals new HP1a links to chromatin organization and function.

          Abstract

          Heterochromatin protein 1 (HP1a) has conserved roles in gene silencing and heterochromatin and is also implicated in transcription, DNA replication, and repair. Here we identify chromatin-associated protein and RNA interactions of HP1a by BioTAP-XL mass spectrometry and sequencing from Drosophila S2 cells, embryos, larvae, and adults. Our results reveal an extensive list of known and novel HP1a-interacting proteins, of which we selected three for validation. A strong novel interactor, dADD1 ( Drosophila ADD1) (CG8290), is highly enriched in heterochromatin , harbors an ADD domain similar to human ATRX, displays selective binding to H3K9me2 and H3K9me3, and is a classic genetic suppressor of position-effect variegation. Unexpectedly, a second hit, HIPP1 (HP1 and insulator partner protein-1) (CG3680), is strongly connected to CP190-related complexes localized at putative insulator sequences throughout the genome in addition to its colocalization with HP1a in heterochromatin. A third interactor, the histone methyltransferase MES-4, is also enriched in heterochromatin. In addition to these protein–protein interactions, we found that HP1a selectively associated with a broad set of RNAs transcribed from repetitive regions. We propose that this rich network of previously undiscovered interactions will define how HP1a complexes perform their diverse functions in cells and developing organisms.

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          Most cited references74

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          TANDEM: matching proteins with tandem mass spectra.

          Tandem mass spectra obtained from fragmenting peptide ions contain some peptide sequence specific information, but often there is not enough information to sequence the original peptide completely. Several proprietary software applications have been developed to attempt to match the spectra with a list of protein sequences that may contain the sequence of the peptide. The application TANDEM was written to provide the proteomics research community with a set of components that can be used to test new methods and algorithms for performing this type of sequence-to-data matching. The source code and binaries for this software are available at http://www.proteome.ca/opensource.html, for Windows, Linux and Macintosh OSX. The source code is made available under the Artistic License, from the authors.
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            Comprehensive analysis of the chromatin landscape in Drosophila

            Summary Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which impact cell differentiation, gene regulation and other key cellular processes. We present a genome-wide chromatin landscape for Drosophila melanogaster based on 18 histone modifications, summarized by 9 prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNaseI hypersensitivity, GRO-seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements, and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions, and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.
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              Heterochromatin and epigenetic control of gene expression.

              Eukaryotic DNA is organized into structurally distinct domains that regulate gene expression and chromosome behavior. Epigenetically heritable domains of heterochromatin control the structure and expression of large chromosome domains and are required for proper chromosome segregation. Recent studies have identified many of the enzymes and structural proteins that work together to assemble heterochromatin. The assembly process appears to occur in a stepwise manner involving sequential rounds of histone modification by silencing complexes that spread along the chromatin fiber by self-oligomerization, as well as by association with specifically modified histone amino-terminal tails. Finally, an unexpected role for noncoding RNAs and RNA interference in the formation of epigenetic chromatin domains has been uncovered.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                1 July 2014
                : 28
                : 13
                : 1445-1460
                Affiliations
                [1 ]Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
                [2 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
                [3 ]Institute of Molecular and Cellular Biology, Novosibirsk 630090, Russia;
                [4 ]Department of Biology, Tufts University, Medford, Massachusetts 02155, USA;
                [5 ]Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
                [6 ]Hematology/Oncology Program, Children’s Hospital, Boston, Massachusetts 02115, USA
                Author notes
                Article
                8711660
                10.1101/gad.241950.114
                4083088
                24990964
                7c734e5e-cdec-4512-840e-c0811838dff1
                © 2014 Alekseyenko et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 21 March 2014
                : 2 June 2014
                Page count
                Pages: 16
                Categories
                Research Paper

                hp1a,chip,formaldehyde cross-linking,lc-ms/ms,bayesian analysis

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