Single Nucleotide Polymorphisms with Cis-Regulatory Effects on Long Non-Coding Transcripts in Human Primary Monocytes

We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10−7 to 9.5×10−89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

[1]  Pedro G. Ferreira,et al.  Transcriptome and genome sequencing uncovers functional variation in humans , 2013, Nature.

[2]  P. Wittkopp,et al.  Sources of bias in measures of allele-specific expression derived from RNA-seq data aligned to a single reference genome , 2013, BMC Genomics.

[3]  Jingyuan Fu,et al.  Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression , 2013, PLoS genetics.

[4]  Andreas Ziegler,et al.  Genome-Wide Haplotype Analysis of Cis Expression Quantitative Trait Loci in Monocytes , 2013, PLoS genetics.

[5]  P. Deloukas,et al.  Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression , 2012, PloS one.

[6]  J. Danesh,et al.  Large-scale association analysis identifies new risk loci for coronary artery disease , 2012, Nature Genetics.

[7]  David G. Knowles,et al.  The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression , 2012, Genome research.

[8]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[9]  J. Reifman,et al.  A new strategy to reduce allelic bias in RNA-Seq readmapping , 2012, Nucleic acids research.

[10]  P. Deloukas,et al.  Integrating Genome-Wide Genetic Variations and Monocyte Expression Data Reveals Trans-Regulated Gene Modules in Humans , 2011, PLoS genetics.

[11]  Alison Abbott,et al.  Europe to map the human epigenome , 2011, Nature.

[12]  Howard Y. Chang,et al.  Molecular mechanisms of long noncoding RNAs. , 2011, Molecular cell.

[13]  Ryan A. Flynn,et al.  A unique chromatin signature uncovers early developmental enhancers in humans , 2011, Nature.

[14]  Mousheng Xu,et al.  Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. , 2010, Human molecular genetics.

[15]  R. Young,et al.  Histone H3K27ac separates active from poised enhancers and predicts developmental state , 2010, Proceedings of the National Academy of Sciences.

[16]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[17]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

[18]  G. Kreiman,et al.  Widespread transcription at neuronal activity-regulated enhancers , 2010, Nature.

[19]  Nathaniel D Heintzman,et al.  Finding distal regulatory elements in the human genome. , 2009, Current opinion in genetics & development.

[20]  Mathieu Blanchette,et al.  Global patterns of cis variation in human cells revealed by high-density allelic expression analysis , 2009, Nature Genetics.

[21]  John C. Marioni,et al.  Effect of read-mapping biases on detecting allele-specific expression from RNA-sequencing data , 2009, Bioinform..

[22]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[23]  M. Baumgartner,et al.  Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype–phenotype correlations , 2009, Human mutation.

[24]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[25]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[26]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[27]  K. Dewar,et al.  Targeted screening of cis-regulatory variation in human haplotypes. , 2008, Genome research.

[28]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[29]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[30]  Nathaniel D. Heintzman,et al.  Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome , 2007, Nature Genetics.

[31]  Thomas J. Hudson,et al.  Cis-Acting Regulatory Variation in the Human Genome , 2004, Science.

[32]  Ziwei Yu,et al.  [Treatment of the paranasal sinuses mycosis with endoscopic sinus surgery]. , 2002, Lin chuang er bi yan hou ke za zhi = Journal of clinical otorhinolaryngology.

[33]  Jeannie T. Lee,et al.  Tsix, a gene antisense to Xist at the X-inactivation centre , 1999, Nature Genetics.

[34]  Carolyn J. Brown,et al.  A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome , 1991, Nature.

[35]  Melissa C. Greven,et al.  An integrated encyclopedia of DNA elements in the human genome , 2014 .

[36]  Jessica Nordlund,et al.  Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation. , 2009, Genome research.