The thyroid hormone receptor (TR) binds the genome in absence of hormone and represses transcription through recruitment of co-repressor proteins. Binding of hormone results in dissociation of co-repressors and recruitment of co-activators leading to transcriptional activation. Until recently this exchange of co-regulators was thought primarily to take place while TR is stably bound to the genome, emphasizing TR as a direct transcriptional repressor when thyroid hormone concentrations are low. Using a genomics based approach we have recently discovered that TR can be hormone dependently recruited to the genome, suggesting that in absence of thyroid hormone TR is not necessarily engaged in direct transcriptional repression. Thus our current understanding of thyroid hormone regulation of gene transcription is far more complex than previously anticipated and must be reevaluated. This project aims to combine genetics and genomics based approaches to decipher the mechanisms of thyroid hormone regulation of gene transcription. Specifically, hepatic genome-wide histone acetylation and methylation will be probed in mouse models for disruptive interaction between co-repressor NCoR and TR. This will be combined with genome-wide profiles of co-activator recruitment and RNA-seq analysis. We predict that these studies will uncover novel mechanism for TR regulation of transcription, which may have profound implication on diseases related to TR mutations and thyroid hormonal dysfunction.
|Effective start/end date||01/01/2016 → 30/06/2018|