ODP483 Histone deacetylase 3 plays an important role in cerebellar developmental defects induced by hypothyroidism

Abstract

Abstract Background Properly organized transcriptional regulation is responsible for the organogenesis of central nervous system including the cerebellum. Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. In the absence of ligand, thyroid hormone receptor binds to co-repressor complexes which contain histone deacetylase (HDAC) 3, and acts as a transcriptional repressor. Although histone acetylation status is highly correlated with transcriptional regulation, the role of histone acetylation and deacetylation in cerebellar development in vivo remains largely unknown. In this study, we aim to study the role of HDAC3 in the cerebellar developmental defects induced by hypothyroidism. Methods Perinatal hypothyroidism and cerebellar defects were induced by an anti-thyroid agent propylthiouracil in mice. The mice were further treated with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed by three behavioral tests. Cerebellums are subjected to RT-PCR and chromatin immunoprecipitation for acetylated histone H3. Results Treatment with HDAC3 inhibitor significantly alleviated motor coordination defects in perinatally hypothyroid mice, suggesting that the enzymatic activity of HDAC3 contributes to motor coordination defects in these mice. These findings were associated with a partial rescue of small cerebellar size in hypothyroidism. In addition, HDAC3 inhibitor increased mRNA levels of cerebellar thyroid hormone responsive genes. The increase in mRNA levels was correlated with an increase in histone acetylation status at these gene loci. Conclusion HDAC3 plays an important role in cerebellar developmental defects induced by hypothyroidism, at least partly by histone deacetylation and transcriptional repression of thyroid hormone-target genes. Presentation: No date and time listed