Genome-Wide Association between Transcription Factor Expression and Chromatin Accessibility Reveals Regulators of Chromatin Accessibility
Fig 2
Association between motif accessibility and mRNA expression for the putative chromatin accessibility regulator EBF1.
Three different regression models (a-c) were used to compute association p-values between the accessibility of a given TF motif (here EBF1) and mRNA expression for each of the assayed 15K protein-coding genes. Results are visualized as qq-plots showing the -log10 transformed p-values. (a) Association p-values obtained using standard linear regression. Due to confounding, p-values are strongly inflated and EBF1 motif accessibility does not show strong association with EBF1 expression compared to other genes. (b) The linear mixed model (LMM) successfully corrects for confounding, with most p-values following the null distribution as expected. The association between EBF1 motif accessibility and EBF1 expression now ranks second among all genes and first among all TFs, although it does not pass the Bonferroni significance threshold. (c) Additionally controlling for the first principal component of the motif accessibility matrix corrects for a strong batch effect (Methods), which further improves the signal. Using this approach, EBF1 motif accessibility showed the strongest association precisely with EBF1 expression (i.e., the gene-level CAR rank equals one), suggesting that EBF1 may be a CAR, in agreement with the literature [22]. As a further illustration for the improvements achieved using the mixed model approach S1 Fig shows the analogous plot for FOXA1, the first discovered pioneer factor [4,5].