Functional definition of thyroid hormone response elements based on a synthetic STARR-seq screen

When bound to thyroid hormone, the nuclear receptor TRα1 activates the transcription of a number of genes in many cell types. It mainly acts by binding DNA as an heterodimer with RXRs at specific response elements related to the DR4 consensus sequence. However, the number of DR4-like elements in the genome exceed by far the number of occupied sites, indicating that minor variations in nucleotides composition deeply influence the DNA-binding capacity and transactivation activity of TRα1. An improved protocol of synthetic STARR-seq was used to quantitatively assess the transcriptional activity of thousands of synthetic sites in parallel. This functional screen highlights a strong correlation between the affinity of the heterodimers for DNA and their capacity to mediate the thyroid hormone response.