Extensive relationship between antisense transcription and alternative splicing in the human genome.

To analyze the relationship between antisense transcription and alternative splicing, we developed a computational approach for the detection of antisense-correlated exon splicing events using Affymetrix exon array data. Our analysis of expression data from 176 lymphoblastoid cell lines revealed that the majority of expressed sense-antisense genes exhibited alternative splicing events that were correlated to the expression of the antisense gene. Most of these events occurred in areas of sense-antisense (SAS) gene overlap, which were significantly enriched in both exons and nucleosome occupancy levels relative to nonoverlapping regions of the same genes. Nucleosome occupancy was highly correlated with Pol II abundance across overlapping regions and with concomitant increases in local alternative exon usage. These results are consistent with an antisense transcription-mediated mechanism of splicing regulation in normal human cells. A comparison of the prevalence of antisense-correlated splicing events between individuals of Mormon versus African descent revealed population-specific events that may indicate the continued evolution of new SAS loci. Furthermore, the presence of antisense transcription was correlated to alternative splicing across multiple metazoan species, suggesting that it may be a conserved mechanism contributing to splicing regulation.

[1]  N. Friedman,et al.  Comprehensive comparative analysis of strand-specific RNA sequencing methods , 2010, Nature Methods.

[2]  Ting Wang,et al.  ENCODE whole-genome data in the UCSC Genome Browser , 2009, Nucleic Acids Res..

[3]  Donny D. Licatalosi,et al.  RNA processing and its regulation: global insights into biological networks , 2010, Nature Reviews Genetics.

[4]  Daria A. Gaykalova,et al.  Mechanism of chromatin remodeling and recovery during passage of RNA polymerase II , 2009, Nature Structural &Molecular Biology.

[5]  J. Mattick,et al.  Nucleosomes are preferentially positioned at exons in somatic and sperm cells , 2009, Cell cycle.

[6]  Noah Spies,et al.  Biased chromatin signatures around polyadenylation sites and exons. , 2009, Molecular cell.

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

[8]  G. Ast,et al.  Chromatin organization marks exon-intron structure , 2009, Nature Structural &Molecular Biology.

[9]  M. Laan,et al.  Natural antisense transcript of natriuretic peptide precursor A (NPPA): structural organization and modulation of NPPA expression , 2009, BMC Molecular Biology.

[10]  T. Borodina,et al.  Transcriptome analysis by strand-specific sequencing of complementary DNA , 2009, Nucleic acids research.

[11]  Manuel de la Mata,et al.  Control of alternative splicing through siRNA-mediated transcriptional gene silencing , 2009, Nature Structural &Molecular Biology.

[12]  Johnf . Thompson,et al.  Virtual Terminator nucleotides for next generation DNA sequencing , 2009, Nature Methods.

[13]  Ryan D. Morin,et al.  Next-generation tag sequencing for cancer gene expression profiling. , 2009, Genome research.

[14]  Yuzhuo Wang,et al.  A Novel Protein Isoform of the Multicopy Human NAIP Gene Derives from Intragenic Alu SINE Promoters , 2009, PloS one.

[15]  J. Kawai,et al.  The regulated retrotransposon transcriptome of mammalian cells , 2009, Nature Genetics.

[16]  Dennis B. Troup,et al.  NCBI GEO: archive for high-throughput functional genomic data , 2008, Nucleic Acids Res..

[17]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[18]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[19]  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.

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

[21]  A. G. de Herreros,et al.  A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. , 2008, Genes & development.

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

[23]  Tyson A. Clark,et al.  Evaluation of genetic variation contributing to differences in gene expression between populations. , 2008, American journal of human genetics.

[24]  O. Griffith,et al.  ALEXA: a microarray design platform for alternative expression analysis , 2008, Nature Methods.

[25]  M. Eileen Dolan,et al.  A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity , 2007, Proceedings of the National Academy of Sciences.

[26]  Carlos Bustamante,et al.  Backtracking determines the force sensitivity of RNAP II in a factor-dependent manner , 2007, Nature.

[27]  John D. Storey,et al.  Gene-expression variation within and among human populations. , 2007, American journal of human genetics.

[28]  Joshua T. Burdick,et al.  Common genetic variants account for differences in gene expression among ethnic groups , 2007, Nature Genetics.

[29]  James P. Orengo,et al.  Alternative splicing in disease. , 2007, Advances in experimental medicine and biology.

[30]  Paulo P. Amaral,et al.  Androgen responsive intronic non-coding RNAs , 2007, BMC Biology.

[31]  K. Neugebauer,et al.  Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells , 2006, Nature Structural &Molecular Biology.

[32]  X. Shirley Liu,et al.  Genome-wide in silico identification and analysis of cis natural antisense transcripts (cis-NATs) in ten species , 2006, Nucleic acids research.

[33]  Sin Lam Tan,et al.  Complex Loci in Human and Mouse Genomes , 2006, PLoS genetics.

[34]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.

[35]  S. Salzberg,et al.  The Transcriptional Landscape of the Mammalian Genome , 2005, Science.

[36]  Philipp Kapranov,et al.  Examples of the complex architecture of the human transcriptome revealed by RACE and high-density tiling arrays. , 2005, Genome research.

[37]  L. Hurst,et al.  Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense-antisense transcripts. , 2005, Trends in genetics : TIG.

[38]  K. Shearwin,et al.  Transcriptional interference--a crash course. , 2005, Trends in genetics : TIG.

[39]  S. Chuang,et al.  Identification and characterization of a novel gene Saf transcribed from the opposite strand of Fas. , 2005, Human molecular genetics.

[40]  Yoshihide Hayashizaki,et al.  Disclosing hidden transcripts: mouse natural sense-antisense transcripts tend to be poly(A) negative and nuclear localized. , 2005, Genome research.

[41]  Rotem Sorek,et al.  Naturally occurring antisense: transcriptional leakage or real overlap? , 2005, Genome research.

[42]  Paul T. Groth,et al.  The ENCODE (ENCyclopedia Of DNA Elements) Project , 2004, Science.

[43]  Sergio Verjovski-Almeida,et al.  Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer , 2004, Oncogene.

[44]  M. Garcia-Blanco,et al.  Alternative splicing in disease and therapy , 2004, Nature Biotechnology.

[45]  J. Mattick.  RNA regulation: a new genetics? , 2004, Nature Reviews Genetics.

[46]  Ben Lehner,et al.  In search of antisense. , 2004, Trends in biochemical sciences.

[47]  Xiaoqiu Huang,et al.  Over 20% of human transcripts might form sense-antisense pairs. , 2004, Nucleic acids research.

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

[49]  S. Kuersten,et al.  The power of the 3′ UTR: translational control and development , 2003, Nature Reviews Genetics.

[50]  P. Viganò,et al.  Different basic fibroblast growth factor and fibroblast growth factor-antisense expression in eutopic endometrial stromal cells derived from women with and without endometriosis. , 2003, The Journal of clinical endocrinology and metabolism.

[51]  D. Higgs,et al.  Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease , 2003, Nature Genetics.

[52]  Guoying Liu,et al.  NetAffx: Affymetrix probesets and annotations , 2003, Nucleic Acids Res..

[53]  Philip Lijnzaad,et al.  The Ensembl genome database project , 2002, Nucleic Acids Res..

[54]  C. Vaquero,et al.  Do natural antisense transcripts make sense in eukaryotes? , 1998, Gene.

[55]  J. SantaLucia,et al.  A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[56]  C. Milcarek,et al.  Expression of the thyroid hormone receptor gene, erbAalpha, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. , 1997, Nucleic acids research.

[57]  S. P. Wright,et al.  Adjusted P-values for simultaneous inference , 1992 .

[58]  J. Battey,et al.  N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts , 1990, Molecular and cellular biology.

[59]  D. E. Roberts,et al.  The Upper Tail Probabilities of Spearman's Rho , 1975 .