Abstract 2068 BDNF is transcriptionally regulated by estradiol and lncRNA HOTAIR

Brain-derived neurotrophic factor (BDNF) serves as a crucial neurotransmitter responsible for growth and maintenance of neurons. Dysregulation of BDNF has been associated with neurodegenerative disorders and other human diseases. Estradiol (E2) is a well-established regulator of the differentiation and adaptability of hippocampal neurons. In this study, we investigated the BDNF gene regulation under basal conditions and under stimuli such as E2. Our findings indicate that E2 induces the expression of BDNF both in vitro, using HT22 cells (hippocampal neuronal cells), and in vivo, within the brains of ovariectomized mice treated with E2. ChIP analysis reveals that estrogen receptors (ERα and ERβ) become enriched at the BDNF promoter in the presence of E2. Moreover, several key factors such as ER-coregulators (e.g., CBP/p300, MLL3), histone acetylation, H3K4-trimethylation, and RNA polymerase II levels were also increased at the BDNF promoter in an E2-dependent manner. In the absence of E2 (under basal conditions), we discovered that the long noncoding RNA HOTAIR, along with its interacting partners PRC2 and LSD1 complexes, binds to the BDNF promoter, effectively repressing BDNF expression. Knocking down HOTAIR alleviated this repression, leading to an increase in BDNF expression. Furthermore, the levels of HOTAIR-interacting partners, EZH2 and LSD1, were reduced at the BDNF promoter upon HOTAIR knockdown, revealing that HOTAIR plays a regulatory role in modulating histone modifications at the BDNF promoter to affect gene expression. Additionally, we demonstrated that E2-induced BDNF expression is mediated by the displacement of repressive factors, EZH2 and LSD1, from the BDNF promoter, followed by the recruitment of active transcription machinery. These results shed light on the intricate mechanisms governing BDNF gene regulation under both basal conditions and in the presence of a positive regulator such as E2 in neuronal cells.