Institut de Génomique Fonctionnelle de Lyon, Université Claude Bernard Lyon I, CNRS UMR 5242, INRAE USC 1370 Ecole Normale Supérieure de Lyon, 69364 Lyon, France.
Endocrinology. 2022 Aug 1;163(8). doi: 10.1210/endocr/bqac084.
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 a heterodimer with retinoid X receptors 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 self-transcribing active regulatory region sequencing 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.
当与甲状腺激素结合时，核受体 TRα1 会激活许多细胞类型中许多基因的转录。它主要通过与视黄酸 X 受体形成异二聚体结合 DNA 来发挥作用，该异二聚体在与 DR4 共有序列相关的特定反应元件上结合 DNA。然而，基因组中 DR4 样元件的数量远远超过了被占据的位点数量，这表明核苷酸组成的微小变化会深刻影响 TRα1 的 DNA 结合能力和转录激活活性。我们使用改进的合成自我转录活性调控区测序方案来定量评估数千个合成位点的转录活性。该功能筛选突出了异二聚体与 DNA 的亲和力与其介导甲状腺激素反应的能力之间的强相关性。
