One goal of human genetics is to understand how the information for precise
and dynamic gene expression programs is encoded in the genome. The interactions
of transcription factors (TFs) with DNA regulatory elements clearly play an
important role in determining gene expression outputs, yet the regulatory logic
underlying functional transcription factor binding is poorly understood. Many
studies have focused on characterizing the genomic locations of TF binding, yet
it is unclear to what extent TF binding at any specific locus has functional
consequences with respect to gene expression output. To evaluate the context of
functional TF binding we knocked down 59 TFs and chromatin modifiers in one
HapMap lymphoblastoid cell line. We then identified genes whose expression was
affected by the knockdowns. We intersected the gene expression data with
transcription factor binding data (based on ChIP-seq and DNase-seq) within 10
kb of the transcription start sites of expressed genes. This combination of
data allowed us to infer functional TF binding. On average, 14.7% of genes
bound by a factor were differentially expressed following the knockdown of that
factor, suggesting that most interactions between TF and chromatin do not
result in measurable changes in gene expression levels of putative target
genes. We found that functional TF binding is enriched in regulatory elements
that harbor a large number of TF binding sites, at sites with predicted higher
binding affinity, and at sites that are enriched in genomic regions annotated
as active enhancers.Comment: 30 pages, 6 figures (7 supplemental figures and 6 supplemental tables
available upon request to [email protected]). Submitted to PLoS
Genetic
