School of Computer Engineering, Nanyang Technological University, Singapore.
Proteome Sci. 2012 Jun 21;10 Suppl 1(Suppl 1):S11. doi: 10.1186/1477-5956-10-S1-S11.
The regulatory mechanism of recombination is a fundamental problem in genomics, with wide applications in genome-wide association studies, birth-defect diseases, molecular evolution, cancer research, etc. In mammalian genomes, recombination events cluster into short genomic regions called "recombination hotspots". Recently, a 13-mer motif enriched in hotspots is identified as a candidate cis-regulatory element of human recombination hotspots; moreover, a zinc finger protein, PRDM9, binds to this motif and is associated with variation of recombination phenotype in human and mouse genomes, thus is a trans-acting regulator of recombination hotspots. However, this pair of cis and trans-regulators covers only a fraction of hotspots, thus other regulators of recombination hotspots remain to be discovered. In this paper, we propose an approach to predicting additional trans-regulators from DNA-binding proteins by comparing their enrichment of binding sites in hotspots. Applying this approach on newly mapped mouse hotspots genome-wide, we confirmed that PRDM9 is a major trans-regulator of hotspots. In addition, a list of top candidate trans-regulators of mouse hotspots is reported. Using GO analysis we observed that the top genes are enriched with function of histone modification, highlighting the epigenetic regulatory mechanisms of recombination hotspots.
重组的调控机制是基因组学中的一个基本问题，在全基因组关联研究、出生缺陷疾病、分子进化、癌症研究等领域有广泛的应用。在哺乳动物基因组中，重组事件聚集在短的基因组区域，称为“重组热点”。最近，在热点中富集的一个 13 -mer 基序被鉴定为人类重组热点的顺式调控元件的候选物；此外，锌指蛋白 PRDM9 结合到这个基序上，并与人类和小鼠基因组中重组表型的变异相关，因此是重组热点的反式作用调控因子。然而，这对顺式和反式调控因子仅覆盖了热点的一部分，因此其他的重组热点调控因子仍有待发现。在本文中，我们提出了一种通过比较 DNA 结合蛋白在热点中的结合位点丰度来预测额外反式调控因子的方法。将该方法应用于全基因组新定位的小鼠热点上，我们证实 PRDM9 是热点的主要反式调控因子。此外，还报告了一组小鼠热点的顶级候选反式调控因子。通过 GO 分析，我们观察到顶级基因富集了组蛋白修饰的功能，突出了重组热点的表观遗传调控机制。
