Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

ABSTRACTTransposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C (chromosome conformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r = 0.9, P < 2.2 × 1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation with some remote functional DNA elements like enhancers and promoters (Enhancer: hESC: r = 0.997, P = 2.3 × 10−4; IMR90: r = 0.934, P = 2 × 10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes.

[1]  A. Smit.  Interspersed repeats and other mementos of transposable elements in mammalian genomes. , 1999, Current opinion in genetics & development.

[2]  Y. Quentin,et al.  Fusion of a free left Alu monomer and a free right Alu monomer at the origin of the Alu family in the primate genomes. , 1992, Nucleic acids research.

[3]  Deepak Grover,et al.  Nonrandom distribution of alu elements in genes of various functional categories: insight from analysis of human chromosomes 21 and 22. , 2003, Molecular biology and evolution.

[4]  H. Kazazian.  Mobile Elements: Drivers of Genome Evolution , 2004, Science.

[5]  Michael D. Wilson,et al.  Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages , 2012, Cell.

[6]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[7]  G. Bourque,et al.  Transposable elements have rewired the core regulatory network of human embryonic stem cells , 2010, Nature Genetics.

[8]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[9]  P. Stenson,et al.  A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease , 2005, Human Genetics.

[10]  Kyudong Han,et al.  The novel MER transposon-derived miRNAs in human genome. , 2013, Gene.

[11]  Yves Quentin,et al.  Origin of the Alu family: a family of Alu-like monomers gave birth to the left and the right arms of the Alu elements , 1992, Nucleic Acids Res..

[12]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[13]  Lee E. Edsall,et al.  Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. , 2010, Cell stem cell.

[14]  J. Bennetzen,et al.  A unified classification system for eukaryotic transposable elements , 2007, Nature Reviews Genetics.

[15]  A. Rösen‐Wolff,et al.  Alu repeat-induced deletions in chronic granulomatous disease: a cause not only for p67-phox, but also for p47-phox deficiency , 2013, Annals of Hematology.

[16]  J. Brookfield.  Selection on Alu sequences? , 2001, Current Biology.

[17]  V. Kapitonov,et al.  The age of Alu subfamilies , 2004, Journal of Molecular Evolution.

[18]  Eytan Domany,et al.  Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes , 2006, BMC Genomics.

[19]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

[20]  Vetle I. Torvik,et al.  Alu elements within human mRNAs are probable microRNA targets. , 2006, Trends in genetics : TIG.

[21]  H. Firpi,et al.  Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers , 2011, Nucleic acids research.

[22]  M. Soares,et al.  Epigenomic analysis of Alu repeats in human ependymomas , 2010, Proceedings of the National Academy of Sciences.

[23]  Tony Kouzarides,et al.  Histone H3 lysine 4 methylation patterns in higher eukaryotic genes , 2004, Nature Cell Biology.

[24]  Vincent J. Lynch,et al.  Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals , 2011, Nature Genetics.

[25]  W. Sung,et al.  ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing , 2010, Genome Biology.

[26]  Yi Xing,et al.  Diverse Splicing Patterns of Exonized Alu Elements in Human Tissues , 2008, PLoS genetics.

[27]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[28]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[29]  J. Ule.  Alu elements: at the crossroads between disease and evolution , 2013, Biochemical Society transactions.

[30]  F. Pagani,et al.  Interaction of hnRNPA1/A2 and DAZAP1 with an Alu-Derived Intronic Splicing Enhancer Regulates ATM Aberrant Splicing , 2011, PloS one.

[31]  Wendy A Bickmore,et al.  Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. , 2010, Molecular cell.

[32]  J. Banerji,et al.  A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes , 1983, Cell.

[33]  E. Liu,et al.  Evolution of the mammalian transcription factor binding repertoire via transposable elements. , 2008, Genome research.

[34]  A. Bird,et al.  CpG islands and the regulation of transcription. , 2011, Genes & development.

[35]  V. Corces,et al.  Enhancer function: new insights into the regulation of tissue-specific gene expression , 2011, Nature Reviews Genetics.

[36]  S. Tonegawa,et al.  A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene , 1983, Cell.

[37]  C. Feschotte.  Transposable elements and the evolution of regulatory networks , 2008, Nature Reviews Genetics.

[38]  Dan Graur,et al.  Alu-containing exons are alternatively spliced. , 2002, Genome research.

[39]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[40]  W. D. Laat,et al.  A Decade of 3c Technologies: Insights into Nuclear Organization References , 2022 .

[41]  Eugene Berezikov,et al.  Evolution of microRNA diversity and regulation in animals , 2011, Nature Reviews Genetics.

[42]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[43]  M. G. Kidwell,et al.  PERSPECTIVE: TRANSPOSABLE ELEMENTS, PARASITIC DNA, AND GENOME EVOLUTION , 2001, Evolution; international journal of organic evolution.

[44]  Samir K. Brahmachari,et al.  Alu repeat analysis in the complete human genome: trends and variations with respect to genomic composition , 2004, Bioinform..

[45]  Michael R. Green,et al.  Transcriptional regulatory elements in the human genome. , 2006, Annual review of genomics and human genetics.

[46]  Inna Dubchak,et al.  VISTA Enhancer Browser—a database of tissue-specific human enhancers , 2006, Nucleic Acids Res..

[47]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[48]  Thierry Heidmann,et al.  Human LINE retrotransposons generate processed pseudogenes , 2000, Nature Genetics.

[49]  J. Jurka,et al.  Duplication, coclustering, and selection of human Alu retrotransposons. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[51]  David Haussler,et al.  Thousands of human mobile element fragments undergo strong purifying selection near developmental genes , 2007, Proceedings of the National Academy of Sciences.

[52]  James J. Cai,et al.  Widespread establishment and regulatory impact of Alu exons in human genes , 2011, Proceedings of the National Academy of Sciences.

[53]  M. Batzer,et al.  Alu repeats and human genomic diversity , 2002, Nature Reviews Genetics.

[54]  S. Pfaff,et al.  Transposable elements as genetic regulatory substrates in early development. , 2013, Trends in cell biology.

[55]  Stuart L Schreiber,et al.  Methylation of histone H3 K4 mediates association of the Isw1p ATPase with chromatin. , 2003, Molecular cell.

[56]  David A. Orlando,et al.  Mediator and Cohesin Connect Gene Expression and Chromatin Architecture , 2010, Nature.

[57]  M. Batzer,et al.  The impact of retrotransposons on human genome evolution , 2009, Nature Reviews Genetics.

[58]  J. Landry,et al.  Long Terminal Repeats Are Used as Alternative Promoters for the Endothelin B Receptor and Apolipoprotein C-I Genes in Humans* , 2001, The Journal of Biological Chemistry.

[59]  Xi Chen,et al.  Evolutionary rate of human tissue-specific genes are related with transposable element insertions , 2012, Genetica.

[60]  G. Mosialos,et al.  Genomic Analysis Reveals a Novel Nuclear Factor-κB (NF-κB)-binding Site in Alu-repetitive Elements* , 2011, The Journal of Biological Chemistry.

[61]  Mary C. Rykowski,et al.  Human genome organization: Alu, LINES, and the molecular structure of metaphase chromosome bands , 1988, Cell.

[62]  Stuart L. Schreiber,et al.  Active genes are tri-methylated at K4 of histone H3 , 2002, Nature.

[63]  Chad A. Cowan,et al.  Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species. , 2010, Genome research.

[64]  B. Ren,et al.  Genome organization and long-range regulation of gene expression by enhancers. , 2013, Current opinion in cell biology.

[65]  Andrew B. Conley,et al.  Epigenetic regulation of transposable element derived human gene promoters. , 2011, Gene.

[66]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[67]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[68]  C. Walsh,et al.  Cytosine methylation and the ecology of intragenomic parasites. , 1997, Trends in genetics : TIG.

[69]  A. Tanay,et al.  Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture , 2011, Nature Genetics.

[70]  P. Kavathas,et al.  Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene , 1993, Molecular and cellular biology.

[71]  A. Nekrutenko,et al.  Transposable elements are found in a large number of human protein-coding genes. , 2001, Trends in genetics : TIG.

[72]  Weidong Tian,et al.  Combining Hi-C data with phylogenetic correlation to predict the target genes of distal regulatory elements in human genome , 2013, Nucleic acids research.

[73]  A. Federico,et al.  Alu-element insertion in an OPA1 intron sequence associated with autosomal dominant optic atrophy , 2010, Molecular vision.

[74]  Feng Cui,et al.  Impact of Alu repeats on the evolution of human p53 binding sites , 2011, Biology Direct.

[75]  John F. Y. Brookfield,et al.  The ecology of the genome — mobile DNA elements and their hosts , 2005, Nature Reviews Genetics.

[76]  V. Babich,et al.  Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters. , 2004, Genomics.

[77]  P. Carpena,et al.  The Biased Distribution of Alus in Human Isochores Might Be Driven by Recombination , 2005, Journal of Molecular Evolution.

[78]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

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

[80]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[81]  M. Speek,et al.  Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation , 2011, PloS one.

[82]  G. Glazko,et al.  Origin of a substantial fraction of human regulatory sequences from transposable elements. , 2003, Trends in genetics : TIG.

[83]  Raymond K. Auerbach,et al.  Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation , 2012, Cell.

[84]  J. Jurka,et al.  Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[85]  T. Bestor.  The host defence function of genomic methylation patterns. , 1998, Novartis Foundation symposium.