Gestational choline supplementation improves cross-generational mood by epigenetic upregulation of Nr3c1 [RNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84315 | GEO | 2021/09/01
REPOSITORIES: GEO
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Project description:Environmental cues during gestation could exert transgenerational effects on behavior mainly through changes in epigenetic marks such as DNA methylation. However, the role of histone modifications in the inheritance of acquired phenotypes remains largely unknown in mammals. Here, we report that gestational choline supplementation (GCS) in maternal mice exerts anxiolytic effects on male offspring across 2 generations. Correspondingly, GCS-induced H3K9 hyperacetylation in the Nr3c1 promoter in male hippocampus leads to upregulation of Nr3c1 and its encoded protein, glucocorticoid receptor (GR), across 2 generations through the male germline. Furthermore, inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) function restored GCS-induced epigenetic and behavioral alterations, suggesting that CBP function as a HAT to increase Nr3c1 expression through H3K9 hyperacetylation. Thus, GCS-induced GR upregulation through CBP-mediated H3K9 hyperacetylation in the Nr3c1 promoter is associated with anxiolytic behavior in male offspring, highlighting the role of histone modification in acquired phenotypes across mammalian generations.
2021-09-01 | GSE84316 | GEO
Project description:Environmental cues during gestation could exert transgenerational effects on behavior mainly through changes in epigenetic marks such as DNA methylation. However, the role of histone modifications in the inheritance of acquired phenotypes remains largely unknown in mammals. Here, we report that gestational choline supplementation (GCS) in maternal mice exerts anxiolytic effects on male offspring across 2 generations. Correspondingly, GCS-induced H3K9 hyperacetylation in the Nr3c1 promoter in male hippocampus leads to upregulation of Nr3c1 and its encoded protein, glucocorticoid receptor (GR), across 2 generations through the male germline. Furthermore, inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) function restored GCS-induced epigenetic and behavioral alterations, suggesting that CBP function as a HAT to increase Nr3c1 expression through H3K9 hyperacetylation. Thus, GCS-induced GR upregulation through CBP-mediated H3K9 hyperacetylation in the Nr3c1 promoter is associated with anxiolytic behavior in male offspring, highlighting the role of histone modification in acquired phenotypes across mammalian generations.
2021-09-01 | GSE84314 | GEO
Project description:Glucocorticoids (GCs) are among the most effective and frequently prescribed anti-inflammatory drugs in dermatology. The effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor (TF). Despite the well-studied therapeutic and adverse effects of GCs, the molecular signature of GC/GR in human skin is largely unknown. Here, we present a bioinformatics analysis of the human skin transcriptome induced by the glucocorticoid clobetasol propionate (CBP). Full thickness arm skin biopsies were obtained from a cohort of 17 healthy volunteers balanced in sex and race (African-American and Caucasian) 24 hrs after single CBP topical application. Non-treated skin from the same volunteers served as control. Analyses of differentially expressed genes (DEGs) and gene set enrichments (GSE) from RNASeq reflected anti-inflammatory, metabolic and atrophogenic effects of GCs in skin. More than 40% of all DEGs were non-coding RNAs, including long non-coding RNAs (lncRNAs) suggesting that GR effects in skin may extend towards regulation at the post-transcriptional level. Furthermore, we observed sexual and racial dimorphism in the CBP response including a shift towards IFNg/IFNa and IL6/JAK/STAT3 signaling in female skin; and an overall larger response to CBP (increased number of DEGs and increased induction of some GR-target genes) in African-American skin. Weighted gene co-expression network analysis (WGCNA) unveiled a regulatory network comprising 41 TFs, with network hub TFs enriched for direct GR targets and ~ 260 of their target genes that were enriched for the majority of altered functional pathways of the entire CBP transcriptome. Interestingly, ~ 80% of these TFs involved in the regulation of circadian clock, metabolism, and development have been associated with skin aging supporting at the molecular level the known similarities between skin chronically treated with GCs and aged skin. Overall, these findings indicate that GR acts as a master regulator of gene expression in skin via multiple mechanisms including regulation of expression of noncoding RNAs and multiple core TFs
2018-10-04 | GSE120783 | GEO
Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function was unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Nut’s major function is therefore to use the ubiquitous HATs p300/CBP to direct a cell-type specific histone hyperacetylation. Its ectopic activity in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-02 | PXD008727 | Pride
Project description:The Glucocorticoid receptor (GR/NR3C1) is expressed in almost all immune cells. Glucocorticoids (GCs) are potent regulators of inflammation with effects mainly immunosuppressive. While, GCs have pleiotropic effects on Macrophages exhibiting complex properties with enhancing as well as suppressive effects on inflammatory processes depending on their stage of differentiation and activation, the mechanisms of GCs actions on Monocytes and Macrophages and their contribution to systemic anti-inflammatory effects remain unclear. Previously we have demonstrated that NLRP3 expression is induced by GCs in macrophages differentiated from monocytes-THP-1 but not in monocytes. These findings raise the possibility that the stage of myeloid differentiation and the cellular environment dictates the actions of GR from a pro- or anti-inflammatory perspective. Moreover, our preliminary results using the same cell line THP-1 show that the differentiation process from monocytes to macrophages also is related with the downregulation of GR induced by dex.
2020-01-27 | GSE135130 | GEO
Project description:In zebrafish, ovulated oocytes contain both cortisol deposited from the maternal circulation and maternal mRNA for the glucocorticoid receptor (gr mRNA), which is spread as granular structures throughout the central ooplasm. At the 1-cell stage (0.2 hpf), this transcript is relocated by streamers in the blastodisc area and equally partitioned among blastomeres. At 15 hpf, it is replaced by the zygotic transcript. Morpholino knockdown was applied to block translation (grATG1MO or MO2-nr3c1 and grATG2MO or MO3-nr3c1) of both maternal and zygotic gr transcripts, while a missplicing morpholino (grmismMO or MO4-nr3c1) was used to block post-transcriptionally the zygotic transcript alone. MO2-nr3c1 and MO3-nr3c1 (but not MO4-nr3c1) treatment produced craniofacial and caudal malformations in 1-dpf embryos and 5-dpf larvae, which were also affected by pericardial oedema, persistent yolk sac, reduced subintestinal veins, altered neurogenesis and uninflated swim bladder. Such effects were rescued with trout gr2 mRNA. Pangenomic microarray analysis revealed that 114 and 37 highly expressed transcripts were up- and down-regulated, respectively, by maternal GR protein deficiency in 5-hpf embryos. Similar alterations were found at 10 hpf. These effects were confirmed by real-time PCR of 2 up- (casp8, grp1 and igf2a) and 1 down-regulated transcripts (mcm6) evaluated at 4, 8 and 12 hpf. As the contents of transcripts were modified already at 4 hpf, it seems that the lack of GR affects both ways the molecular machinery for the degradation of maternal mRNAs. These results indicate that the maternal gr transcript participates in the maternal programming of zebrafish development. MO2-nr3c1 morphants were compared with MO2-nr3c1-5m morphants at 5 hpf and 10 hpf. MO2-nr3c1 morphants were compared with wild type (WT) at 5 hpf and 10 hpf. MO2-nr3c1 is a morpholino selected to knockdown translation of gr mRNA. MO2-nr3c1-5m is a specific control morpholino.
2011-11-16 | E-GEOD-25517 | biostudies-arrayexpress
Project description:Histone hyperacetylation is thought to drive the replacement of histones by transition proteins that occurs in elongating spermatids after a general shut-down of transcription. The molecular machineries underlying this histone hyperacetylation remain still undefined. Here we focused our attention on the role of Cbp and p300 in histone hyperacetylation and in the preceding late gene transcriptional activity in elongating spermatids. A strategy was designed to partially deplete Cbp and p300 in elongating spermatids. These cells progressed normally through spermiogenesis and showed normal histone hyperacetylation and removal. However, a genome-wide transcriptomic analysis, performed in the round and elongating spermatids, revealed the existence of a gene regulatory circuit encompassing genes presenting high expression levels in pre-meiotic cells, undergoing a repressed state in spermatocytes and early post-meiotic cells, but becoming reactivated in elongating spermatids, just prior to the global shut-down of transcription. Interestingly, this group of genes was over-represented within the genes affected by Cbp/p300 knock-down and were all involved in metabolic remodelling. This study revealed the occurrence of a tightly regulated Cbp/p300-dependent gene expression program that drives a specific metabolic state both in progenitor spermatogenic cells and in late transcriptionally active spermatids and confirmed a special link between Cpb/p300 and cell metabolism programming previously shown in somatic cells. Total RNA were obtained from post meiotic male germ cells (round spermatids and condensing spermatids) of adult mice either wild-type or with a double knock down of Cbp/P300 in post-meiotic cells. In each experiments, 6 replicates of each genotype and cell type were used.
2014-03-12 | E-GEOD-55767 | biostudies-arrayexpress
Project description:Glucocorticoids (GCs) reduce the expression of many genes induced in inflammatory conditions in vivo or by pro-inflammatory stimuli in vitro acting on the Glucocorticoid receptor (GR/NR3C1). However, GCs have pleiotropic effects on the immune system. Monocytes and macrophages are important cells of the innate immune system, exhibiting complex properties with enhancing as well as suppressive effects on inflammatory processes depending on their stage of activation and differentiation. Macrophages contribute to host defense, tissue remodeling and wound healing The mechanisms of GCs actions on monocytes and macrophages and their contribution to systemic anti-inflammatory effects remain unclear. These effects on activation GCs in monocytes and macrophages were investigated using the human monocytic cell line THP-1 and differentiation protocol PMA. Monocytes-THP1 and macrophages derived-monocytes were exposed for 6 hours to 100 nM of dexamethasone (Dex) and analyzed by microarrays. In macrophages-derived monocytes with respect to monocytes-THP-1, the number of genes differentially regulated was almost twice, among these, genes related with pro-inflammatory pathways, like TNFa, CXCL1 and GZMA. Interestingly, one of the genes differentially regulated (decreased) in macrophages exposed to Dex was the GR itself. If this effect modifies the inflammatory function of macrophages derived-monocyte is a question that will be evaluated through this study.
2020-01-27 | GSE135165 | GEO
Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function is unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Our results bring the first evidence of Nut’s function in spermatogenic cells where it uses the ubiquitous HATs p300/CBP to direct a cell-type specific histone H4 hyperacetylation. The ectopic activity of Nut in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain-binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-15 | GSE111931 | GEO
Project description:CBP/p300 are transcription co-activators whose binding is a signature of enhancers, cis-regulatory elements that control patterns of gene expression in multicellular organisms. Active enhancers produce bi-directional enhancer RNAs (eRNAs) and display CBP/p300 dependent histone acetylation. Here, we demonstrate that CBP binds directly to RNAs in vivo and in vitro. RNAs bound to CBP in vivo include a large number of eRNAs. Using steady-state histone acetyltransferase (HAT) assays we show that an RNA binding region in the HAT domain of CBP—a regulatory motif unique to CBP/p300—allows RNA to stimulate CBP’s HAT activity. At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA-dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression. By interacting directly with CBP, eRNAs contribute to the unique chromatin structure at active enhancers, which in turn is required for regulation of target genes.
2017-01-12 | GSE75684 | GEO