HMGN1 Modulates Nucleosome Occupancy and DNase I Hypersensitivity at the CpG Island Promoters of Embryonic Stem Cells

ABSTRACT Chromatin structure plays a key role in regulating gene expression and embryonic differentiation; however, the factors that determine the organization of chromatin around regulatory sites are not fully known. Here we show that HMGN1, a nucleosome-binding protein ubiquitously expressed in vertebrate cells, preferentially binds to CpG island-containing promoters and affects the organization of nucleosomes, DNase I hypersensitivity, and the transcriptional profile of mouse embryonic stem cells and neural progenitors. Loss of HMGN1 alters the organization of an unstable nucleosome at transcription start sites, reduces the number of DNase I-hypersensitive sites genome wide, and decreases the number of nestin-positive neural progenitors in the subventricular zone (SVZ) region of mouse brain. Thus, architectural chromatin-binding proteins affect the transcription profile and chromatin structure during embryonic stem cell differentiation.

[1]  M. Bustin,et al.  Chromosomal Protein HMGN1 Enhances the Heat Shock-induced Remodeling of Hsp70 Chromatin* , 2008, Journal of Biological Chemistry.

[2]  Richard A Young,et al.  Control of the Embryonic Stem Cell State , 2011, Cell.

[3]  Michael Bustin,et al.  Effects of HMGN variants on the cellular transcription profile , 2011, Nucleic acids research.

[4]  Po-yi Ho,et al.  Histone H1 Depletion Impairs Embryonic Stem Cell Differentiation , 2012, PLoS genetics.

[5]  Samuel H. Wilson,et al.  HMGN1 Protein Regulates Poly(ADP-ribose) Polymerase-1 (PARP-1) Self-PARylation in Mouse Fibroblasts* , 2012, The Journal of Biological Chemistry.

[6]  M. Bustin,et al.  Developmental role of HMGN proteins in Xenopus laevis , 2003, Mechanisms of Development.

[7]  Dustin E. Schones,et al.  The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice* , 2011, The Journal of Biological Chemistry.

[8]  R. Young,et al.  A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells , 2007, Cell.

[9]  M. Bustin,et al.  High-mobility group proteins 14 and 17 maintain the timing of early embryonic development in the mouse. , 2001, Developmental biology.

[10]  T. Misteli,et al.  Competition between histone H1 and HMGN proteins for chromatin binding sites , 2002, EMBO reports.

[11]  E. Rand,et al.  Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation , 2012, Nature Communications.

[12]  Dustin E. Schones,et al.  Genomic Profiling of HMGN1 Reveals an Association with Chromatin at Regulatory Regions , 2010, Molecular and Cellular Biology.

[13]  B. Pugh,et al.  Genome-wide Nucleosome Specificity and Directionality of Chromatin Remodelers , 2012, Cell.

[14]  M. Bustin,et al.  The Nucleosome Binding Protein HMGN1 Interacts with PCNA and Facilitates Its Binding to Chromatin , 2012, Molecular and Cellular Biology.

[15]  L. Kay,et al.  Architecture of the high mobility group nucleosomal protein 2-nucleosome complex as revealed by methyl-based NMR , 2011, Proceedings of the National Academy of Sciences.

[16]  J. Workman,et al.  Nucleosome positioning: multiple mechanisms toward a unifying goal. , 2012, Molecular cell.

[17]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[18]  T. Misteli,et al.  Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. , 2006, Developmental cell.

[19]  M. Gut,et al.  Supplemental information for : “ CpG islands and GC content dictate nucleosome depletion in a transcription independent manner at mammalian promoters ” , 2012 .

[20]  M. Bustin,et al.  The footprint of chromosomal proteins HMG-14 and HMG-17 on chromatin subunits. , 1994, Journal of molecular biology.

[21]  Michael Bustin,et al.  Chromosomal protein HMGN1 enhances the rate of DNA repair in chromatin , 2003, The EMBO journal.

[22]  E. Meshorer,et al.  Chromatin plasticity and genome organization in pluripotent embryonic stem cells. , 2010, Current opinion in cell biology.

[23]  J. McNally,et al.  The interaction of NSBP1/HMGN5 with nucleosomes in euchromatin counteracts linker histone-mediated chromatin compaction and modulates transcription. , 2009, Molecular cell.

[24]  M. Bianchi,et al.  HMG proteins: dynamic players in gene regulation and differentiation. , 2005, Current opinion in genetics & development.

[25]  Tatiana A. Tatusova,et al.  NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy , 2011, Nucleic Acids Res..

[26]  L. Mahadevan,et al.  Signalling to chromatin through post-translational modifications of HMGN. , 2010, Biochimica et biophysica acta.

[27]  Michael Bustin,et al.  Regulation of DNA-Dependent Activities by the Functional Motifs of the High-Mobility-Group Chromosomal Proteins , 1999, Molecular and Cellular Biology.

[28]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[29]  Mo Li,et al.  Navigating the epigenetic landscape of pluripotent stem cells , 2012, Nature Reviews Molecular Cell Biology.

[30]  Michael Bustin,et al.  The dynamics of histone H1 function in chromatin. , 2005, Molecular cell.

[31]  J. T. Kadonaga,et al.  HMGN proteins act in opposition to ATP-dependent chromatin remodeling factors to restrict nucleosome mobility. , 2009, Molecular cell.

[32]  C. Woodcock,et al.  Role of linker histone in chromatin structure and function: H1 stoichiometry and nucleosome repeat length , 2006, Chromosome Research.

[33]  Kairong Cui,et al.  H3.3/H2A.Z double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions in the human genome , 2009, Nature Genetics.

[34]  S. Cherukuri,et al.  Developmental function of HMGN proteins. , 2010, Biochimica et biophysica acta.

[35]  M. Bustin,et al.  Metastable Macromolecular Complexes Containing High Mobility Group Nucleosome-binding Chromosomal Proteins in HeLa Nuclei* , 2002, The Journal of Biological Chemistry.

[36]  M. Bustin,et al.  HMG chromosomal proteins in development and disease. , 2007, Trends in cell biology.

[37]  M. Bustin,et al.  Increased tumorigenicity and sensitivity to ionizing radiation upon loss of chromosomal protein HMGN1. , 2005, Cancer research.

[38]  Chen Zeng,et al.  A clustering approach for identification of enriched domains from histone modification ChIP-Seq data , 2009, Bioinform..

[39]  Crispin J. Miller,et al.  Simpleaffy: a BioConductor package for Affymetrix Quality Control and data analysis , 2005, Bioinform..

[40]  M. Bustin,et al.  Cell cycle-dependent binding of HMGN proteins to chromatin. , 2008, Molecular biology of the cell.

[41]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[42]  M. Bustin Chromatin unfolding and activation by HMGN(*) chromosomal proteins. , 2001, Trends in biochemical sciences.

[43]  C. Allis,et al.  Genome-wide “Re”-Modeling of Nucleosome Positions , 2011, Cell.

[44]  Elias T. Zambidis,et al.  HMGA1 Reprograms Somatic Cells into Pluripotent Stem Cells by Inducing Stem Cell Transcriptional Networks , 2012, PloS one.

[45]  H. Weintraub,et al.  Isolation of a subclass of nuclear proteins responsible for conferring a DNase I-sensitive structure on globin chromatin. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Benjamin M. Bolstad,et al.  affy - analysis of Affymetrix GeneChip data at the probe level , 2004, Bioinform..

[47]  M. Bustin,et al.  The Nucleosome Binding Protein HMGN3 Modulates the Transcription Profile of Pancreatic β Cells and Affects Insulin Secretion , 2009, Molecular and Cellular Biology.

[48]  R. Hock,et al.  Binding and interplay of HMG proteins on chromatin: lessons from live cell imaging. , 2010, Biochimica et biophysica acta.

[49]  Judith A. Blake,et al.  The Mouse Genome Database: Genotypes, Phenotypes, and Models of Human Disease , 2012, Nucleic Acids Res..

[50]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[51]  M. Bustin Chromatin unfolding and activation by HMGN , 2001 .

[52]  M. Bustin,et al.  Determinants of histone H1 mobility and chromatin binding in living cells , 2006, Nature Structural &Molecular Biology.

[53]  E. Eyras,et al.  Nucleosome-driven transcription factor binding and gene regulation. , 2013, Molecular cell.

[54]  J. Mallm,et al.  Genome-wide nucleosome positioning during embryonic stem cell development , 2012, Nature Structural &Molecular Biology.

[55]  E. Arenas,et al.  An Efficient Method for the Derivation of Mouse Embryonic Stem Cells , 2006, Stem cells.