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Status |
Public on Feb 22, 2024 |
Title |
Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis [ATAC-Seq] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
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Overall design |
Analysis of chromatin accessibility in HNF4a+ hepatocytes isolated from control and NCOR1/2 dKO livers.
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Contributor(s) |
Hauck AK, Lazar MA, Mehmood R |
Citation(s) |
38622413 |
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Submission date |
Jun 06, 2023 |
Last update date |
Nov 06, 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) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (6)
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This SubSeries is part of SuperSeries: |
GSE234234 |
Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis |
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Relations |
BioProject |
PRJNA980596 |