Genetic Landscape of Open Chromatin in Yeast

Chromatin regulation underlies a variety of DNA metabolism processes, including transcription, recombination, repair, and replication. To perform a quantitative genetic analysis of chromatin accessibility, we obtained open chromatin profiles across 96 genetically different yeast strains by FAIRE (formaldehyde-assisted isolation of regulatory elements) assay followed by sequencing. While 5~10% of open chromatin region (OCRs) were significantly affected by variations in their underlying DNA sequences, subtelomeric areas as well as gene-rich and gene-poor regions displayed high levels of sequence-independent variation. We performed quantitative trait loci (QTL) mapping using the FAIRE signal for each OCR as a quantitative trait. While individual OCRs were associated with a handful of specific genetic markers, gene expression levels were associated with many regulatory loci. We found multi-target trans-loci responsible for a very large number of OCRs, which seemed to reflect the widespread influence of certain chromatin regulators. Such regulatory hotspots were enriched for known regulatory functions, such as recombinational DNA repair, telomere replication, and general transcription control. The OCRs associated with these multi-target trans-loci coincided with recombination hotspots, telomeres, and gene-rich regions according to the function of the associated regulators. Our findings provide a global quantitative picture of the genetic architecture of chromatin regulation. Quantitative trait loci (QTL) mapping is a genetic approach that allows the identification of genetic factors underlying a phenotype of interest. Genomic technologies such as DNA microarray and next-generation sequencing provide data that can be used for the analysis of multiple molecular phenotypes. For example, the expression levels of thousands of genes can be associated with subject-specific genome-wide genetic information in expression QTL mapping. Similarly, the genetic regulation of transcription factor binding or epigenetic mechanisms such as DNA methylation or chromatin structure has begun to be investigated. In particular, the mechanisms controlling chromatin accessibility have attracted special interest due to their importance in a variety of DNA regulation processes including recombination, repair, replication, and transcription. In this work, we sought to dissect the genetic architecture of chromatin accessibility regulation by harnessing the power of genetic and genomic techniques. By analyzing open (accessible) chromatin maps of multiple yeast individuals in association with their genetic backgrounds, we were able to characterize the regulatory structure of chromatin traits versus that of gene expression. Importantly, we observed that the genetic loci responsible for multiple open chromatin regions were enriched for known regulatory factors.