Cis-acting single nucleotide polymorphisms alter MicroRNA-mediated regulation of human brain-expressed transcripts

被引:6
作者
Ramachandran, Shyam [1 ]
Coffin, Stephanie L. [1 ]
Tang, Tin-Yun [2 ]
Jobaliya, Chintan D. [1 ,3 ]
Spengler, Ryan M. [4 ]
Davidson, Beverly L. [1 ,5 ,6 ]
机构
[1] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
[2] Howard Hughes Med Inst, Howard Hughes Med Inst Med Res Fellow, Chevy Chase, MD USA
[3] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Human Pluripotent Stem Cell Core, Philadelphia, PA 19104 USA
[4] Univ Michigan, Dept Internal Med, Div Hematol, Div Oncol, Ann Arbor, MI 48109 USA
[5] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[6] Univ Penn, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
HUMAN GENE-EXPRESSION; RNA-BINDING PROTEIN; MIRNA TARGET SITES; ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE; RISK; SNPS; IDENTIFICATION; DISORDERS; DATABASE;
D O I
10.1093/hmg/ddw317
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Substantial variability exists in the presentation of complex neurological disorders, and the study of single nucleotide polymorphisms (SNPs) has shed light on disease mechanisms and pathophysiological variability in some cases. However, the vast majority of disease-linked SNPs have unidentified pathophysiological relevance. Here, we tested the hypothesis that SNPs within the miRNA recognition element (MRE; the region of the target transcript to which the miRNA binds) can impart changes in the expression of those genes, either by enhancing or reducing transcript and protein levels. To test this, we cross-referenced 7,153 miRNA-MRE brain interactions with the SNP database (dbSNP) to identify candidates, and functionally assessed 24 SNPs located in the 3'UTR or the coding sequence (CDS) of targets. For over half of the candidates tested, SNPs either enhanced (4 genes) or disrupted (10 genes) miRNA binding and target regulation. Additionally, SNPs causing a shift from a common to rare codon within the CDS facilitated miRNA binding downstream of the SNP, dramatically repressing target gene expression. The biological activity of the SNPs on miRNA regulation was also confirmed in induced pluripotent stem cell (iPSC) lines. These studies strongly support the notion that SNPs in the 3'UTR or the coding sequence of disease-relevant genes may be important in disease pathogenesis and should be reconsidered as candidate modifiers.
引用
收藏
页码:4939 / 4950
页数:12
相关论文
共 62 条
[1]   Predicting effective microRNA target sites in mammalian mRNAs [J].
Agarwal, Vikram ;
Bell, George W. ;
Nam, Jin-Wu ;
Bartel, David P. .
ELIFE, 2015, 4
[2]  
Al-Chalabi Ammar, 2000, Current Opinion in Neurology, V13, P397, DOI 10.1097/00019052-200008000-00006
[3]   Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression [J].
Almlof, Jonas Carlsson ;
Lundmark, Per ;
Lundmark, Anders ;
Ge, Bing ;
Maouche, Seraya ;
Goering, Harald H. H. ;
Liljedahl, Ulrika ;
Enstrom, Camilla ;
Brocheton, Jessy ;
Proust, Carole ;
Godefroy, Tiphaine ;
Sambrook, Jennifer G. ;
Jolley, Jennifer ;
Crisp-Hihn, Abigail ;
Foad, Nicola ;
Lloyd-Jones, Heather ;
Stephens, Jonathan ;
Gwilliam, Rhian ;
Rice, Catherine M. ;
Hengstenberg, Christian ;
Samani, Nilesh J. ;
Erdmann, Jeanette ;
Schunkert, Heribert ;
Pastinen, Tomi ;
Deloukas, Panos ;
Goodall, Alison H. ;
Ouwehand, Willem H. ;
Cambien, Francois ;
Syvanen, Ann-Christine .
PLOS ONE, 2012, 7 (12)
[4]   Gene Ontology: tool for the unification of biology [J].
Ashburner, M ;
Ball, CA ;
Blake, JA ;
Botstein, D ;
Butler, H ;
Cherry, JM ;
Davis, AP ;
Dolinski, K ;
Dwight, SS ;
Eppig, JT ;
Harris, MA ;
Hill, DP ;
Issel-Tarver, L ;
Kasarskis, A ;
Lewis, S ;
Matese, JC ;
Richardson, JE ;
Ringwald, M ;
Rubin, GM ;
Sherlock, G .
NATURE GENETICS, 2000, 25 (01) :25-29
[5]   MicroRNAs: Target Recognition and Regulatory Functions [J].
Bartel, David P. .
CELL, 2009, 136 (02) :215-233
[6]   PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways [J].
Bhattacharya, Anindya ;
Ziebarth, Jesse D. ;
Cui, Yan .
NUCLEIC ACIDS RESEARCH, 2014, 42 (D1) :D86-D91
[7]   Transcriptome-wide Discovery of microRNA Binding Sites in Human Brain [J].
Boudreau, Ryan L. ;
Jiang, Peng ;
Gilmore, Brian L. ;
Spengler, Ryan M. ;
Tirabassi, Rebecca ;
Nelson, Jay A. ;
Ross, Christopher A. ;
Xing, Yi ;
Davidson, Beverly L. .
NEURON, 2014, 81 (02) :294-305
[8]   Cis and Trans Effects of Human Genomic Variants on Gene Expression [J].
Bryois, Julien ;
Buil, Alfonso ;
Evans, David M. ;
Kemp, John P. ;
Montgomery, Stephen B. ;
Conrad, Donald F. ;
Ho, Karen M. ;
Ring, Susan ;
Hurles, Matthew ;
Deloukas, Panos ;
Smith, George Davey ;
Dermitzakis, Emmanouil T. .
PLOS GENETICS, 2014, 10 (07)
[9]   Scalable GMP compliant suspension culture system for human ES cells [J].
Chen, Vincent C. ;
Couture, Sylvana M. ;
Ye, Jingjing ;
Lin, Ziguang ;
Hua, Giau ;
Huang, Hsiao-I P. ;
Wu, Jun ;
Hsu, David ;
Carpenter, Melissa K. ;
Couture, Larry A. .
STEM CELL RESEARCH, 2012, 8 (03) :388-402
[10]   Gene expression profiling in human neurodegenerative disease [J].
Cooper-Knock, Johnathan ;
Kirby, Janine ;
Ferraiuolo, Laura ;
Heath, Paul R. ;
Rattray, Magnus ;
Shaw, Pamela J. .
NATURE REVIEWS NEUROLOGY, 2012, 8 (09) :518-530