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Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci

Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation sta...

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Autores principales: Susetyo, Alvin, Ishii, Sumiyasu, Fujiwara, Yuki, Amano, Izuki, Koibuchi, Noriyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319938/
https://www.ncbi.nlm.nih.gov/pubmed/35887216
http://dx.doi.org/10.3390/ijms23147869
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author Susetyo, Alvin
Ishii, Sumiyasu
Fujiwara, Yuki
Amano, Izuki
Koibuchi, Noriyuki
author_facet Susetyo, Alvin
Ishii, Sumiyasu
Fujiwara, Yuki
Amano, Izuki
Koibuchi, Noriyuki
author_sort Susetyo, Alvin
collection PubMed
description Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with transcriptional regulation, its role in cerebellar development remains largely unknown. We aimed to study whether the cerebellar developmental defects induced by perinatal hypothyroidism can be rescued by treatment with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed using three behavioral tests. The cerebella were subjected to RT-qPCR and chromatin immunoprecipitation assays for acetylated histone H3. The treatment with RGFP966 partially reversed the cerebellar morphological defects in perinatal hypothyroid mice. These findings were associated with the alleviation of motor coordination defects in these mice. In addition, the RGFP966 administration increased the mRNA levels of cerebellar thyroid hormone-responsive genes. These increases were accompanied by augmented histone acetylation status at these gene loci. These findings indicate that HDAC3 plays an important role in the cerebellar developmental defects induced by perinatal hypothyroidism. The HDAC3 inhibitor might serve as a novel therapeutic agent for hypothyroidism-induced cerebellar defects by acetylating histone tails and stimulating transcription at thyroid hormone-responsive gene loci.
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spelling pubmed-93199382022-07-27 Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci Susetyo, Alvin Ishii, Sumiyasu Fujiwara, Yuki Amano, Izuki Koibuchi, Noriyuki Int J Mol Sci Article Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with transcriptional regulation, its role in cerebellar development remains largely unknown. We aimed to study whether the cerebellar developmental defects induced by perinatal hypothyroidism can be rescued by treatment with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed using three behavioral tests. The cerebella were subjected to RT-qPCR and chromatin immunoprecipitation assays for acetylated histone H3. The treatment with RGFP966 partially reversed the cerebellar morphological defects in perinatal hypothyroid mice. These findings were associated with the alleviation of motor coordination defects in these mice. In addition, the RGFP966 administration increased the mRNA levels of cerebellar thyroid hormone-responsive genes. These increases were accompanied by augmented histone acetylation status at these gene loci. These findings indicate that HDAC3 plays an important role in the cerebellar developmental defects induced by perinatal hypothyroidism. The HDAC3 inhibitor might serve as a novel therapeutic agent for hypothyroidism-induced cerebellar defects by acetylating histone tails and stimulating transcription at thyroid hormone-responsive gene loci. MDPI 2022-07-17 /pmc/articles/PMC9319938/ /pubmed/35887216 http://dx.doi.org/10.3390/ijms23147869 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Susetyo, Alvin
Ishii, Sumiyasu
Fujiwara, Yuki
Amano, Izuki
Koibuchi, Noriyuki
Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title_full Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title_fullStr Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title_full_unstemmed Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title_short Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
title_sort histone deacetylase 3 inhibitor alleviates cerebellar defects in perinatal hypothyroid mice by stimulating histone acetylation and transcription at thyroid hormone-responsive gene loci
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319938/
https://www.ncbi.nlm.nih.gov/pubmed/35887216
http://dx.doi.org/10.3390/ijms23147869
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