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Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice

Cocaine epigenetically regulates gene expression via changes in histone post-translational modifications (HPTMs). We previously found that the immediate early gene Nr4a1 is epigenetically activated by cocaine in mouse brain reward regions. However, few studies have examined multiple HPTMs at a singl...

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Autores principales: Fischer, Delaney K., Krick, Keegan S., Han, Chloe, Woolf, Morgan T., Heller, Elizabeth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9492678/
https://www.ncbi.nlm.nih.gov/pubmed/36130958
http://dx.doi.org/10.1038/s41598-022-19908-9
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author Fischer, Delaney K.
Krick, Keegan S.
Han, Chloe
Woolf, Morgan T.
Heller, Elizabeth A.
author_facet Fischer, Delaney K.
Krick, Keegan S.
Han, Chloe
Woolf, Morgan T.
Heller, Elizabeth A.
author_sort Fischer, Delaney K.
collection PubMed
description Cocaine epigenetically regulates gene expression via changes in histone post-translational modifications (HPTMs). We previously found that the immediate early gene Nr4a1 is epigenetically activated by cocaine in mouse brain reward regions. However, few studies have examined multiple HPTMs at a single gene. Bivalent gene promoters are simultaneously enriched in both activating (H3K4me3 (K4)) and repressive (H3K27me3 (K27)) HPTMs. As such, bivalent genes are lowly expressed but poised for activity-dependent gene regulation. In this study, we identified K4&K27 bivalency at Nr4a1 following investigator-administered cocaine in male and female mice. We applied sequential chromatin immunoprecipitation and qPCR to define Nr4a1 bivalency and expression in striatum (STR), prefrontal cortex (PFC), and hippocampus (HPC). We used Pearson’s correlation to quantify relationships within each brain region across treatment conditions for each sex. In female STR, cocaine increased Nr4a1 mRNA while maintaining Nr4a1 K4&K27 bivalency. In male STR, cocaine enriched repressive H3K27me3 and K4&K27 bivalency at Nr4a1 and maintained Nr4a1 mRNA. Furthermore, cocaine epigenetically regulated a putative NR4A1 target, Cartpt, in male PFC. This study defined the epigenetic regulation of Nr4a1 in reward brain regions in male and female mice following cocaine, and, thus, shed light on the biological relevance of sex to cocaine use disorder.
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spelling pubmed-94926782022-09-23 Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice Fischer, Delaney K. Krick, Keegan S. Han, Chloe Woolf, Morgan T. Heller, Elizabeth A. Sci Rep Article Cocaine epigenetically regulates gene expression via changes in histone post-translational modifications (HPTMs). We previously found that the immediate early gene Nr4a1 is epigenetically activated by cocaine in mouse brain reward regions. However, few studies have examined multiple HPTMs at a single gene. Bivalent gene promoters are simultaneously enriched in both activating (H3K4me3 (K4)) and repressive (H3K27me3 (K27)) HPTMs. As such, bivalent genes are lowly expressed but poised for activity-dependent gene regulation. In this study, we identified K4&K27 bivalency at Nr4a1 following investigator-administered cocaine in male and female mice. We applied sequential chromatin immunoprecipitation and qPCR to define Nr4a1 bivalency and expression in striatum (STR), prefrontal cortex (PFC), and hippocampus (HPC). We used Pearson’s correlation to quantify relationships within each brain region across treatment conditions for each sex. In female STR, cocaine increased Nr4a1 mRNA while maintaining Nr4a1 K4&K27 bivalency. In male STR, cocaine enriched repressive H3K27me3 and K4&K27 bivalency at Nr4a1 and maintained Nr4a1 mRNA. Furthermore, cocaine epigenetically regulated a putative NR4A1 target, Cartpt, in male PFC. This study defined the epigenetic regulation of Nr4a1 in reward brain regions in male and female mice following cocaine, and, thus, shed light on the biological relevance of sex to cocaine use disorder. Nature Publishing Group UK 2022-09-21 /pmc/articles/PMC9492678/ /pubmed/36130958 http://dx.doi.org/10.1038/s41598-022-19908-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Fischer, Delaney K.
Krick, Keegan S.
Han, Chloe
Woolf, Morgan T.
Heller, Elizabeth A.
Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title_full Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title_fullStr Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title_full_unstemmed Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title_short Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
title_sort cocaine regulation of nr4a1 chromatin bivalency and mrna in male and female mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9492678/
https://www.ncbi.nlm.nih.gov/pubmed/36130958
http://dx.doi.org/10.1038/s41598-022-19908-9
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