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Neonatal Thyroxine Activation Modifies Epigenetic Programming of The Liver

View ORCID ProfileTatiana L. Fonseca, Tzintzuni Garcia, Gustavo W. Fernandes, T. Murlidharan Nair, View ORCID ProfileAntonio C. Bianco
doi: https://doi.org/10.1101/2020.12.07.414938
Tatiana L. Fonseca
1Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
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  • ORCID record for Tatiana L. Fonseca
Tzintzuni Garcia
2Center for Translational Data Science, University of Chicago, Chicago, IL
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Gustavo W. Fernandes
1Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
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T. Murlidharan Nair
3Department of Biological Sciences and CS/Informatics, Indiana University South Bend, South Bend, IN
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Antonio C. Bianco
1Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, IL
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  • For correspondence: abianco@deiodinase.org
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Abstract

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.

Competing Interest Statement

Disclosures: AB is a consultant for Allergan Inc and Synthonics, Inc.; the other authors have nothing to disclose.

Footnotes

  • Disclosures: AB is a consultant for Allergan Inc and Synthonics, Inc.; the other authors have nothing to disclose. The other authors have nothing to disclose.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 08, 2020.
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Neonatal Thyroxine Activation Modifies Epigenetic Programming of The Liver
Tatiana L. Fonseca, Tzintzuni Garcia, Gustavo W. Fernandes, T. Murlidharan Nair, Antonio C. Bianco
bioRxiv 2020.12.07.414938; doi: https://doi.org/10.1101/2020.12.07.414938
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Neonatal Thyroxine Activation Modifies Epigenetic Programming of The Liver
Tatiana L. Fonseca, Tzintzuni Garcia, Gustavo W. Fernandes, T. Murlidharan Nair, Antonio C. Bianco
bioRxiv 2020.12.07.414938; doi: https://doi.org/10.1101/2020.12.07.414938

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