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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
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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.
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Overall design |
mRNA profile, TR beta cistrome and H3K27ac ChIP-seq of hypo- and hyperthyroid state mice livers.
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Contributor(s) |
Shabtai Y, Batmanov K, Nagaraj NK, Forrest D, Cho Y, Lazar M |
Citation(s) |
- Shabtai Y, Nagaraj NK, Batmanov K, Cho YW et al. A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver. Genes Dev 2021 Mar 1;35(5-6):367-378. PMID: 33602873
- Cho YW, Fu Y, Huang CJ, Wu X et al. Thyroid hormone-regulated chromatin landscape and transcriptional sensitivity of the pituitary gland. Commun Biol 2023 Dec 11;6(1):1253. PMID: 38081939
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Submission date |
Oct 19, 2020 |
Last update date |
Jan 02, 2024 |
Contact name |
Mitchell Lazar |
E-mail(s) |
lazar@pennmedicine.upenn.edu
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Organization name |
University of Pennsylvania
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Department |
Perelman School of Medicine
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Lab |
Lazar lab
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Street address |
3400 Civic Center Blvd
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City |
Philadelphia |
State/province |
PA |
ZIP/Postal code |
19104 |
Country |
USA |
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Platforms (1) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (53)
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Relations |
BioProject |
PRJNA669898 |
SRA |
SRP287698 |
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 |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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