Genome-wide cistromes of thyroid hormone receptors alpha and beta in C17.2 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Fabrice Chatonnet
PROVIDER: E-GEOD-38347 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Tagged versions of thyroid hormone receptors alpha (TRa) and beta (TRb) were stably transfected in two C17.2 cell lines, C17.2a and C17.2b, respectively. We performed an affinity-based purification of chromatin (ChAP), and high-throughput sequencing was used to assess binding sites of both receptors (ChAP-Seq). Standard ChIP-Seq for RXR was also performed in C17.2a cells. These data allow us to compare binding sites for both receptors and to conclude that they were only partially redundant, with co-existence of receptor-specific sites.
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Project description:Thyroid hormones (THs) play a critical role in development and throughout adulthood. THs act through the thyroid receptor (TR), which binds to the TH response element (TRE) to regulate the expression of target genes. Although TH action has been studied for decades, surprisingly few TREs have been well validated and characterized. In this study we used chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) to identify TR-binding sites in juvenile (postnatal day 15) mice liver. Microarray analysis revealed twelve TR-binding sites consistent between all analyzed samples. In silico analysis was carried out to search for moderately conserved classic TRE sequences within these novel binding regions, which led to the identification of six candidate TREs within three binding regions. Luciferase reporter assays confirmed the presence of a TRE in the promoter region of DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54) and thyroid hormone responsive SPOT14 (Thrsp). The TR/retinoid X receptor (RXR) heterodimer and RXR homodiner were shown to bind the promoter region of Ddx54 and drive gene expression in the presence of 9-cis-retinoic acid (9cRA). The promoter region of Thrsp was shown to allow binding of the TR/RXR heterodimer, and both T3 and 9cRA were able to significantly increase luciferase activity. The RXR homodimer was also able to bind the response element in the promoter region of Thrsp and increase luciferase activity. Overall, ChIP-chip analysis revealed a relatively limited number of TR-binding sites in juvenile mouse liver despite previous studies showing that numerous genes can be affected by TH disruption at that developmental stage, suggesting that TH action may also be mediated through other intermediates. Collectively the results provide an important step towards characterizing TR-binding sites and identifying the underlying drivers of TR-gene regulation.
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