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Series GSE159648 Query DataSets for GSE159648
Status Public on Jan 01, 2021
Title A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Thyroid hormones (TH) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone- dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TR), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR, and defined high confidence binding sites where TR functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by TH have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, TH regulates gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.
Overall design mRNA profile, TR beta cistrome and H3K27ac ChIP-seq of hypo- and hyperthyroid state mice livers.
Contributor(s) Shabtai Y, Batmanov K, Nagaraj NK, Forrest D, Cho Y, Lazar M
Citation(s) 33602873, 38081939
Submission date Oct 19, 2020
Last update date Jan 02, 2024
Contact name Mitchell Lazar
Organization name University of Pennsylvania
Department Perelman School of Medicine
Lab Lazar lab
Street address 3400 Civic Center Blvd
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (53)
GSM4836770 ChIP-Seq:TR WT rep1
GSM4836771 ChIP-Seq:TR WT rep2
GSM4836772 ChIP-Seq:TR WT rep3
BioProject PRJNA669898
SRA SRP287698

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE159648_Ac_PTU+TH_pooled.tags.ucsc.bigWig 180.5 Mb (ftp)(http) BIGWIG
GSE159648_Ac_PTU_pooled.tags.ucsc.bigWig 87.2 Mb (ftp)(http) BIGWIG
GSE159648_ENSMBL_gene_name_count.txt.gz 3.6 Mb (ftp)(http) TXT
GSE159648_both_OldInput_Union.fully_annotated.peaks.txt.gz 724.4 Kb (ftp)(http) TXT
GSE159648_de_genes_PTU_vs_PTU+TH_4_conditions.tsv.gz 626.6 Kb (ftp)(http) TSV
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