RT Journal Article
SR Electronic
T1 N<span class="sc">eonatal</span> T<span class="sc">hyroxine</span> A<span class="sc">ctivation</span> M<span class="sc">odifies</span> E<span class="sc">pigenetic</span> P<span class="sc">rogramming of</span> T<span class="sc">he</span> L<span class="sc">iver</span>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.07.414938
DO 10.1101/2020.12.07.414938
A1 Tatiana L. Fonseca
A1 Tzintzuni Garcia
A1 Gustavo W. Fernandes
A1 T. Murlidharan Nair
A1 Antonio C. Bianco
YR 2020
UL http://biorxiv.org/content/early/2020/12/08/2020.12.07.414938.abstract
AB 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&lt;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 StatementDisclosures: AB is a consultant for Allergan Inc and Synthonics, Inc.; the other authors have nothing to disclose.