OR10-6 Thyroid Hormone Protects Primary Cortical Neurons Exposed to Hypoxia by Reducing DNA Methylation and Apoptosis
Year: 2019
Type: article
Abstract: Traumatic Brain Injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, when administered shortly after injury, has been shown to promote neural survival in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons, to investigate the effectiveness and mechanism of T3 promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours, in either the presence or absence of T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosin (5-hmc) levels compared to the conditions without T3, and attenuated the hypoxia-induced increase in DNA 5-methylcytosin (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferase, (Dnmt) 3a and Dnmt3b, were downregulated, compared to conditions in the absence of T3. These T3-induced changes may reduce hypoxia-induced DNA de novo methylation. We utilized RNA-seq to characterize T3-regulated genes in cortical neurons under hypoxic conditions, and identified 23 genes that were upregulated and 15 genes that were downregulated. KLF9, krupple-like factor 9, a multifunctional transcription factor that plays a key role in CNS development, was highly upregulated by T3 treatment in hypoxic conditions. We show that knockdown of the KLF9 gene induced early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage and acts through pathways that reduce DNA methylation and apoptosis.
Source: Journal of the Endocrine Society
Institution: University of California, Los Angeles
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,255
OpenAlex ID: W3173573611