The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

Abstract

Estrogen (E 2 ) regulates spermatogenesis, yet its direct target genes have not been identified in the testis. Here, we cloned the proximal 5 0 flanking region of the mouse fatty acid amide hydrolase (faah) gene upstream of the luciferase reporter gene, and demonstrated its promoter activity and E 2 inducibility in primary mouse Sertoli cells. Specific mutations in the E 2 response elements (ERE) of the faah gene showed that two proximal ERE sequences (ERE2/3) are essential for E 2 -induced transcription, and chromatin immunoprecipitation experiments showed that E 2 induced estrogen receptor b binding at ERE2/3 sites in the faah promoter in vivo. Moreover, the histone demethylase LSD1 was found to be associated with ERE2/3 sites and to play a role in mediating E 2 induction of FAAH expression. E 2 induced epigenetic modifications at the faah proximal promoter compatible with transcriptional activation by remarkably decreasing methylation of both DNA at CpG site and histone H3 at lysine 9. Finally, FAAH silencing abolished E 2 protection against apoptosis induced by the FAAH substrate anandamide. Taken together, our results identify FAAH as the first direct target of E 2 .

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

“…Specifically, several studies have demonstrated the ability of estradiol exposure to lead to activation of ERK (Filardo, et al, 2000, Liverman, et al, 2009), increases in sodium gated channel activity (Kow, et al, 2006), as well as increased mRNA levels of FAAH (Cupini, et al, 2006, Greco, et al, 2010, Grimaldi, et al, 2012), the major metabolic regulator of anandamide, an endogenously produced cannabinoid. Furthermore, studies have shown that estradiol treatment leads to elevation in release of CGRP in the dura mater and trigeminal ganglion (Gupta, et al, 2007, Stucky, et al, 2011), key to vasodilation which plays a role in migraine onset and progression (Bigal and Walter, 2014, Goadsby, et al, 1990, Raddant and Russo, 2011).…”

The immunoexpression of androgen receptor, estrogen receptors alpha and beta, vanilloid type 1 receptor and cytochrome p450 aromatase in rats testis chronically treated with letrozole, an aromatase inhibitor

“…TRPV1 was also shown to be expressed in rat testis [17,56]. Germ cells, from spermatogonia to spermatozoa, and Sertoli cells possess a complete biochemical machinery to synthesize, transport, degrade and bind endocannabioids, that can affect male reproductive functions [14,57]. Our results on the immunolocalization of TRPV1 in germ cells, and in residual spermatids cytoplasm of experimental rats are in agreement with the findings of other authors who detected TRPV1 channels in the seminiferous tubules of rat testis using RT-PCR [17,20,56,58,59].…”

“…The biological functions of estrogens are mediated by two types of estrogen receptors: a (ERa) and b (ERb) [6]. ERs regulate gene expression by direct interaction with estrogen-response elements (EREs) in the promoter of target genes [14]. The precise localization of ERs in male gonads remains the subject of numerous studies and topic of many debates [4].…”

Environmental Epigenetics and Effects on Male Fertility

“…In Sertoli cells Rhox5 (reproductive homeobox 5) deletion produces subfertility, increases germ-cell apoptosis, and decreases sperm count and motility through two promoters repressed by DNA methylation (Shanker et al 2008 ). Another interesting observation relates to epigenetic changes produced in the proximal promoter of the fatty acid amide hydrolase (Faah) gene (reduced DNA and histone H3 methylation) in response to estradiol in mouse Sertoli cell cultures (Grimaldi et al 2012 ). Epigenetic changes have also been observed in Leydig cells after exposure to environmental contaminants.…”