Gene Expression Pattern of Histone Acetylation Enzymes Changed in the Hypothalamus of Middle-Aged Female Rats: A Putative Mechanism for Female Reproductive Aging

Abstract

Objective: Female reproductive aging is characterized by reduced responsiveness of the hypothalamus to E2-positive feedback, which can result in alterations of gene expression and luteinizing hormone (LH) surge dysfunction. We hypothesize that age-related changes in E2-responsive gene expression are due to altered histone acetylation by histone deacetylases (HDACs) or estrogen receptor-alpha (ERα) coactivators with histone acetyltransferase (HAT) activity. Methods: In the present study, young and middle-aged female rats were ovariectomized (OVX) and treated with E2 or oil once per day for 2 days. At the time of the expected LH surge, the anterior and posterior hypothalami were dissected, and gene expression of 11 HDACs and 4 ERα coactivators with HAT activity was measured using real-time polymerase chain reaction. Results: In the anterior hypothalamus, age affected the gene expression of 3 HDACs (Hdac3, Hdac5, and Hdac11) and 2 ERα coactivators (Src2 and Crebbp). E2 treatment significantly decreased mRNA levels of 4 HDACs (Hdac4, Hdac5, Hdac10, and Hdac11) and 2 ERα coactivators (Src2 and Crebbp) in young females (3–4 months). However, none of the genes responded to E2 in the middle-aged females (9–11 months), except Hdac10. In the posterior hypothalamus, age influenced Hdac5 and Src1 mRNA expression. E2 treatment increased Hdac4 and Crebbp mRNA levels in the young but not middle-aged females. Conclusions: These data suggest that E2 regulates HDACs and ERα coactivators with HAT activity in an age- and E2-dependent manner, which may contribute to the age-related gene expression changes on the day of LH surge in female reproductive aging. Key words: Aging; Estradiol-Positive Feedback; Estrogen Receptor-Alpha Coactivators; Histone Deacetylases; Hypothalamus