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      Brg1 activates enhancer repertoires to establish B cell identity and modulate cell growth

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          Abstract

          Early B cell development is orchestrated by the combined activities of the transcriptional regulators E2A, EBF1, Foxo1 and Ikaros. However, how the genome-wide binding patterns of these regulators are modulated during B-lineage development remains to be determined. Here, we found that in lymphoid progenitors the chromatin remodeler Brg1 specified the B cell fate. In committed pro-B cells Brg1 regulated Igh locus contraction and controlled Myc expression to modulate the expression of genes that regulate ribosome biogenesis. In committed pro-B cells Brg1 suppressed a pre-B lineage-specific pattern of gene expression. Finally, we found that Brg1 acted mechanistically to establish B cell fate and modulate cell growth by facilitating access of lineage-specific transcription factors to poised enhancer repertoires.

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          Most cited references34

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          Immunogenetics. Chromatin state dynamics during blood formation.

          Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development. Copyright © 2014, American Association for the Advancement of Science.
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            Chromatin remodelling during development.

            New methods for the genome-wide analysis of chromatin are providing insight into its roles in development and their underlying mechanisms. Current studies indicate that chromatin is dynamic, with its structure and its histone modifications undergoing global changes during transitions in development and in response to extracellular cues. In addition to DNA methylation and histone modification, ATP-dependent enzymes that remodel chromatin are important controllers of chromatin structure and assembly, and are major contributors to the dynamic nature of chromatin. Evidence is emerging that these chromatin-remodelling enzymes have instructive and programmatic roles during development. Particularly intriguing are the findings that specialized assemblies of ATP-dependent remodellers are essential for establishing and maintaining pluripotent and multipotent states in cells.
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              MYC as a regulator of ribosome biogenesis and protein synthesis.

              MYC regulates the transcription of thousands of genes required to coordinate a range of cellular processes, including those essential for proliferation, growth, differentiation, apoptosis and self-renewal. Recently, MYC has also been shown to serve as a direct regulator of ribosome biogenesis. MYC coordinates protein synthesis through the transcriptional control of RNA and protein components of ribosomes, and of gene products required for the processing of ribosomal RNA, the nuclear export of ribosomal subunits and the initiation of mRNA translation. We discuss how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                18 April 2015
                18 May 2015
                July 2015
                01 January 2016
                : 16
                : 7
                : 775-784
                Affiliations
                [1 ]Department of Molecular Biology, University of California, San Diego, La Jolla, California, USA
                [2 ]Center for Computational Biology, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA
                [3 ]Center for Hematology and Regenerative Medicine, Karolinska Institute, Huddinge, Sweden
                [4 ]Division of Cellular Immunology, German Cancer Research Center, Im Neuenheimer Field 280, Heidelberg, Germany
                Author notes
                Correspondence should be addressed to C.M. ( murre@ 123456biomail.ucsd.edu )
                Article
                NIHMS677264
                10.1038/ni.3170
                4474778
                25985234
                170952c9-83b7-46a5-b6dc-aff9c1a10461
                History
                Categories
                Article

                Immunology
                Immunology

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