Chromatin organization marks exon-intron structure

An increasing body of evidence indicates that transcription and splicing are coupled, and it is accepted that chromatin organization regulates transcription. Little is known about the cross-talk between chromatin structure and exon-intron architecture. By analysis of genome-wide nucleosome-positioning data sets from humans, flies and worms, we found that exons show increased nucleosome-occupancy levels with respect to introns, a finding that we link to differential GC content and nucleosome-disfavoring elements between exons and introns. Analysis of genome-wide chromatin immunoprecipitation data in humans and mice revealed four specific post-translational histone modifications enriched in exons. Our findings indicate that previously described enrichment of H3K36me3 modifications in exons reflects a more fundamental phenomenon, namely increased nucleosome occupancy along exons. Our results suggest an RNA polymerase II–mediated cross-talk between chromatin structure and exon-intron architecture, implying that exon selection may be modulated by chromatin structure.

[1]  S. Berget,et al.  Exon definition may facilitate splice site selection in RNAs with multiple exons. , 1990, Molecular and cellular biology.

[2]  E N Trifonov,et al.  Splice junctions follow a 205-base ladder. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Berget Exon Recognition in Vertebrate Splicing (*) , 1995, The Journal of Biological Chemistry.

[4]  J. Valcárcel,et al.  Alternative pre-mRNA splicing: the logic of combinatorial control. , 2000, Trends in biochemical sciences.

[5]  B. Graveley Alternative splicing: increasing diversity in the proteomic world. , 2001, Trends in genetics : TIG.

[6]  M. Garcia-Blanco,et al.  The Transcription Elongation Factor CA150 Interacts with RNA Polymerase II and the Pre-mRNA Splicing Factor SF1 , 2001, Molecular and Cellular Biology.

[7]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[8]  A. Kornblihtt,et al.  Transcriptional Activators Differ in Their Abilities to Control Alternative Splicing* , 2002, The Journal of Biological Chemistry.

[9]  K. J. Howe RNA polymerase II conducts a symphony of pre-mRNA processing activities. , 2002, Biochimica et biophysica acta.

[10]  D. Black Mechanisms of alternative pre-messenger RNA splicing. , 2003, Annual review of biochemistry.

[11]  A. Kornblihtt,et al.  A slow RNA polymerase II affects alternative splicing in vivo. , 2003, Molecular cell.

[12]  Gene W. Yeo,et al.  Systematic Identification and Analysis of Exonic Splicing Silencers , 2004, Cell.

[13]  J. Lieb,et al.  Evidence for nucleosome depletion at active regulatory regions genome-wide , 2004, Nature Genetics.

[14]  B. Sarg,et al.  Histone H4-Lysine 20 Monomethylation Is Increased in Promoter and Coding Regions of Active Genes and Correlates with Hyperacetylation* , 2005, Journal of Biological Chemistry.

[15]  Clifford A. Meyer,et al.  Genomic mapping of RNA polymerase II reveals sites of co-transcriptional regulation in human cells , 2005, Genome Biology.

[16]  Edward N Trifonov,et al.  Gene splice sites correlate with nucleosome positions. , 2004, Gene.

[17]  Irene K. Moore,et al.  A genomic code for nucleosome positioning , 2006, Nature.

[18]  M. Yaniv,et al.  The human SWI/SNF subunit Brm is a regulator of alternative splicing , 2006, Nature Structural &Molecular Biology.

[19]  G. Ast,et al.  Comparative analysis identifies exonic splicing regulatory sequences--The complex definition of enhancers and silencers. , 2006, Molecular cell.

[20]  A. Kornblihtt Chromatin, transcript elongation and alternative splicing , 2006, Nature Structural &Molecular Biology.

[21]  Christopher R. Vakoc,et al.  Profile of Histone Lysine Methylation across Transcribed Mammalian Chromatin , 2006, Molecular and Cellular Biology.

[22]  M. Hild,et al.  Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila , 2007, The EMBO journal.

[23]  T. Kouzarides Chromatin Modifications and Their Function , 2007, Cell.

[24]  Gene W. Yeo,et al.  Discovery and Analysis of Evolutionarily Conserved Intronic Splicing Regulatory Elements , 2007, PLoS Genetics.

[25]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[26]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

[27]  Paul Tempst,et al.  Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. , 2007, Molecular cell.

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

[29]  A. Kornblihtt Coupling transcription and alternative splicing. , 2007, Advances in experimental medicine and biology.

[30]  G. Ast,et al.  SR proteins: a foot on the exon before the transition from intron to exon definition. , 2007, Trends in genetics : TIG.

[31]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[32]  J. Berglund,et al.  A comprehensive computational characterization of conserved mammalian intronic sequences reveals conserved motifs associated with constitutive and alternative splicing. , 2007, Genome research.

[33]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[34]  M. Carmo-Fonseca,et al.  The CTD role in cotranscriptional RNA processing and surveillance , 2008, FEBS letters.

[35]  C. Muchardt,et al.  Splicing, transcription, and chromatin: a ménage à trois. , 2008, Current opinion in genetics & development.

[36]  Juliane C. Dohm,et al.  Substantial biases in ultra-short read data sets from high-throughput DNA sequencing , 2008, Nucleic acids research.

[37]  Ian M. Fingerman,et al.  Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4. , 2008, Genes & development.

[38]  Steven M. Johnson,et al.  A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning. , 2008, Genome research.

[39]  Gabor T. Marth,et al.  Whole-genome sequencing and variant discovery in C. elegans , 2008, Nature Methods.

[40]  Nevan J Krogan,et al.  A single SR-like protein, Npl3, promotes pre-mRNA splicing in budding yeast. , 2008, Molecular cell.

[41]  Raja Jothi,et al.  Genome-wide identification of in vivo protein–DNA binding sites from ChIP-Seq data , 2008, Nucleic acids research.

[42]  Dustin E. Schones,et al.  Dynamic Regulation of Nucleosome Positioning in the Human Genome , 2008, Cell.

[43]  S. Batzoglou,et al.  Genome-Wide Analysis of Transcription Factor Binding Sites Based on ChIP-Seq Data , 2008, Nature Methods.

[44]  Stephan C. Schuster,et al.  Nucleosome organization in the Drosophila genome , 2008, Nature.

[45]  Michael Q. Zhang,et al.  Combinatorial patterns of histone acetylations and methylations in the human genome , 2008, Nature Genetics.

[46]  D. Burstein,et al.  Large-scale comparative analysis of splicing signals and their corresponding splicing factors in eukaryotes. , 2007, Genome research.

[47]  George Nikolić,et al.  Ménage à trois. , 2008, Heart & lung : the journal of critical care.

[48]  Yaniv Lubling,et al.  Distinct Modes of Regulation by Chromatin Encoded through Nucleosome Positioning Signals , 2008, PLoS Comput. Biol..

[49]  C. Burge,et al.  Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. , 2008, RNA.

[50]  L. Mahadevan,et al.  Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation , 2007, The EMBO journal.

[51]  Irene K. Moore,et al.  The DNA-encoded nucleosome organization of a eukaryotic genome , 2009, Nature.

[52]  M. Alló,et al.  Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing , 2009, Proceedings of the National Academy of Sciences.

[53]  R. Loomis,et al.  Chromatin binding of SRp20 and ASF/SF2 and dissociation from mitotic chromosomes is modulated by histone H3 serine 10 phosphorylation. , 2009, Molecular cell.

[54]  L. Tora,et al.  Human U1 snRNA forms a new chromatin-associated snRNP with TAF15 , 2009, EMBO reports.

[55]  Melissa J. Moore,et al.  Pre-mRNA Processing Reaches Back toTranscription and Ahead to Translation , 2009, Cell.

[56]  J. Ahringer,et al.  Differential chromatin marking of introns and expressed exons by H3K36me3 , 2008, Nature Genetics.

[57]  Christoforos Nikolaou,et al.  Nucleosome positioning as a determinant of exon recognition , 2009, Nature Structural &Molecular Biology.

[58]  R. Amann,et al.  Predictive Identification of Exonic Splicing Enhancers in Human Genes , 2022 .