Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver.
Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding...
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2021
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oai:doaj.org-article:ebb7253002144d5885d6bce3701f46a02021-12-02T20:02:53ZCorticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver.1553-73901553-740410.1371/journal.pgen.1009737https://doaj.org/article/ebb7253002144d5885d6bce3701f46a02021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009737https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction.Benjamin P FlynnMatthew T BirnieYvonne M KershawAudrys G PauzaSohyoung KimSongjoon BaekMark F RogersAlex R PatersonDiana A StavrevaDavid MurphyGordon L HagerStafford L LightmanBecky L Conway-CampbellPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009737 (2021) |
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DOAJ |
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| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Benjamin P Flynn Matthew T Birnie Yvonne M Kershaw Audrys G Pauza Sohyoung Kim Songjoon Baek Mark F Rogers Alex R Paterson Diana A Stavreva David Murphy Gordon L Hager Stafford L Lightman Becky L Conway-Campbell Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| description |
Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction. |
| format |
article |
| author |
Benjamin P Flynn Matthew T Birnie Yvonne M Kershaw Audrys G Pauza Sohyoung Kim Songjoon Baek Mark F Rogers Alex R Paterson Diana A Stavreva David Murphy Gordon L Hager Stafford L Lightman Becky L Conway-Campbell |
| author_facet |
Benjamin P Flynn Matthew T Birnie Yvonne M Kershaw Audrys G Pauza Sohyoung Kim Songjoon Baek Mark F Rogers Alex R Paterson Diana A Stavreva David Murphy Gordon L Hager Stafford L Lightman Becky L Conway-Campbell |
| author_sort |
Benjamin P Flynn |
| title |
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| title_short |
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| title_full |
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| title_fullStr |
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| title_full_unstemmed |
Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| title_sort |
corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/ebb7253002144d5885d6bce3701f46a0 |
| work_keys_str_mv |
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1718375695541862400 |