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Neonatal thyroxine activation modifies epigenetic programming of the liver.

ABSTRACT: The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1-5 (P1-P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ²= 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.

SUBMITTER: Fonseca TL

PROVIDER: S-EPMC8295303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-18 | GSE162930 | GEO

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ATAC-Seq]

Project description:In the neonatal liver, a peak of type 2 deiodinase (D2) activity accelerates local T3 production and the expression of thyroid hormone (TH)-responsive genes. Here we show that this acute increase in T3 signaling permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increased H3K9me3 levels during post-natal days 1-5 (P1-P5) in discrete chromatin areas, and methylation of 1,508 DNA sites (H-sites) that remained in the adult mouse liver. These sites were associated with 1,551 areas of reduced chromatin accessibility (RCA; Atac-seq) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,525 genes (RNA-seq). There was strong correlation between H-sites and RCA sites (r=0.85; p<0.0002), suggesting a cause-effect relationship. The analysis of chromosome conformation capture (Hi-C) data revealed a set of 57 repressed genes that have a promoter RCA in close contact with an intergenic RCA ~300 Kbp apart, including Foxa2 that plays an important role during development. Thus, the post-natal surge in hepatic D2 activity and TH-signaling prevents discrete DNA methylation and modifies the transcriptome of the adult mouse. This explains how the systemic T3 hormone acts locally during development to define future chromatin accessibility and expression of critically relevant hepatic genes.

2021-06-18 | GSE162929 | GEO

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ChIP-Seq]

2021-06-18 | GSE162887 | GEO

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [RNA-Seq]

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Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver

Project description:Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver

| PRJNA683868 | ENA

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ATAC-Seq]

Project description:Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ATAC-Seq]

| PRJNA683869 | ENA

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ChIP-Seq]

Project description:Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [ChIP-Seq]

| PRJNA683636 | ENA

Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [RNA-Seq]

Project description:Neonatal Thyroxine Activation Modifies Epigenetic Programming Of The Liver [RNA-Seq]

| PRJNA683644 | ENA

NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.

Project description:Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

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Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver.

Project description:Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 mono-, di-, and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator activating signal cointegrator-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch.Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism.

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