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      A novel form of JARID2 is required for differentiation in lineage‐committed cells

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          Abstract

          Polycomb repressive complex‐2 ( PRC2) is a group of proteins that play an important role during development and in cell differentiation. PRC2 is a histone‐modifying complex that catalyses methylation of lysine 27 of histone H3 (H3K27me3) at differentiation genes leading to their transcriptional repression. JARID2 is a co‐factor of PRC2 and is important for targeting PRC2 to chromatin. Here, we show that, unlike in embryonic stem cells, in lineage‐committed human cells, including human epidermal keratinocytes, JARID2 predominantly exists as a novel low molecular weight form, which lacks the N‐terminal PRC2‐interacting domain (ΔN‐ JARID2). We show that ΔN‐ JARID2 is a cleaved product of full‐length JARID2 spanning the C‐terminal conserved jumonji domains. JARID2 knockout in keratinocytes results in up‐regulation of cell cycle genes and repression of many epidermal differentiation genes. Surprisingly, repression of epidermal differentiation genes in JARID2‐null keratinocytes can be rescued by expression of ΔN‐ JARID2 suggesting that, in contrast to PRC2, ΔN‐ JARID2 promotes activation of differentiation genes. We propose that a switch from expression of full‐length JARID2 to ΔN‐ JARID2 is important for the up‐regulation differentiation genes.

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          Most cited references 60

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          TopHat: discovering splice junctions with RNA-Seq

          Motivation: A new protocol for sequencing the messenger RNA in a cell, known as RNA-Seq, generates millions of short sequence fragments in a single run. These fragments, or ‘reads’, can be used to measure levels of gene expression and to identify novel splice variants of genes. However, current software for aligning RNA-Seq data to a genome relies on known splice junctions and cannot identify novel ones. TopHat is an efficient read-mapping algorithm designed to align reads from an RNA-Seq experiment to a reference genome without relying on known splice sites. Results: We mapped the RNA-Seq reads from a recent mammalian RNA-Seq experiment and recovered more than 72% of the splice junctions reported by the annotation-based software from that study, along with nearly 20 000 previously unreported junctions. The TopHat pipeline is much faster than previous systems, mapping nearly 2.2 million reads per CPU hour, which is sufficient to process an entire RNA-Seq experiment in less than a day on a standard desktop computer. We describe several challenges unique to ab initio splice site discovery from RNA-Seq reads that will require further algorithm development. Availability: TopHat is free, open-source software available from http://tophat.cbcb.umd.edu Contact: cole@cs.umd.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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            Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

            Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling, followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs. Copyright 2010 Elsevier Inc. All rights reserved.
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              The Polycomb complex PRC2 and its mark in life.

              Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist - Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes.
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                Author and article information

                Contributors
                a.kanhere@bham.ac.uk
                Journal
                EMBO J
                EMBO J
                10.1002/(ISSN)1460-2075
                EMBJ
                embojnl
                The EMBO Journal
                John Wiley and Sons Inc. (Hoboken )
                0261-4189
                1460-2075
                20 December 2018
                01 February 2019
                20 December 2018
                : 38
                : 3 ( doiID: 10.1002/embj.v38.3 )
                Affiliations
                [ 1 ] School of Biosciences University of Birmingham Birmingham UK
                [ 2 ] Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK
                Author notes
                [* ]Corresponding author. Tel: +44 121 4145896; E‐mail: a.kanhere@ 123456bham.ac.uk
                Article
                EMBJ201798449
                10.15252/embj.201798449
                6356158
                30573669
                © 2018 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 9, Tables: 0, Pages: 13, Words: 10445
                Product
                Funding
                Funded by: Islamic Development Bank (IDB)
                Funded by: University of Birmingham
                Funded by: Wellcome Trust ISSF I (Wellcome ISSF)
                Categories
                Article
                Articles
                Custom metadata
                2.0
                embj201798449
                01 February 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.8 mode:remove_FC converted:01.02.2019

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