High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction.
High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction.
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DOI：
10.1038/s41588-018-0159-z
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发表时间：
2018-08
期刊：
影响因子：
30.8
通讯作者：
Nigrovic PA
中科院分区：
文献类型：
--
作者：
Li G;Martínez-Bonet M;Wu D;Yang Y;Cui J;Nguyen HN;Cunin P;Levescot A;Bai M;Westra HJ;Okada Y;Brenner MB;Raychaudhuri S;Hendrickson EA;Maas RL;Nigrovic PA
全基因组关联研究已经发现了许多与疾病相关的非编码单核苷酸多态，但无法区分功能性SNP(FSNPs)和其他偶然存在于危险基因座内的SNPs。为了应对这一挑战，我们开发了一种无偏见的高通量筛选，它利用IIS类型的酶限制来识别等位调节调节蛋白结合的fSNPs。我们将这种称为SNP-SEQ的方法与侧翼限制增强下拉(FREP)相结合，通过4种调控蛋白RBPJ、RSRC2和FUBP-1/TRAP150来识别3个与疾病相关的fSNP对CD40的调控。将这种方法应用于27个与幼年特发性关节炎相关的基因座，我们确定了148个候选fSNP，其中包括两个通过调节蛋白SATB2和H1.2调节STAT4的FSNP。总之，这些发现确立了串联SNP-seq/FREP在GWAS和疾病机制之间架起桥梁的作用。
Genome wide association studies have identified many disease-associated non-coding single nucleotide polymorphisms, but cannot distinguish functional SNPs (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by 3 disease-associated fSNPs via 4 regulatory proteins, RBPJ, RSRC2, and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.
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