Gene Number: 2099

Location: 6q25.1

Key Functions: Estrogen signaling, reproductive system regulation, bone density maintenance, cardiovascular protection

ESR1 encodes estrogen receptor alpha (ERα), a ligand-activated nuclear hormone receptor that binds estrogens, primarily 17β-estradiol. Upon binding its ligand, ESR1 undergoes conformational changes that enable it to act as a transcription factor, directly binding to estrogen response elements (EREs) in target gene promoters. Through this mechanism, ESR1 modulates the transcription of genes that govern a broad range of physiological processes, including reproductive function, bone metabolism, and cardiovascular homeostasis. In addition to its classical genomic effects, ESR1 also participates in non-genomic signaling pathways through interactions with membrane-associated receptors and cytoplasmic kinases, allowing rapid cellular responses to estrogen.

ESR1 regulates the expression of genes involved in:

1. Reproductive function:ESR1 plays a central role in the development and function of reproductive tissues, including the uterus, ovaries, and mammary glands. It regulates ovulation, endometrial proliferation, and hormone-dependent reproductive cycles, influencing fertility and reproductive health.

2. Bone metabolism:Estrogen signaling via ESR1 is crucial for maintaining bone density. ESR1 activation promotes osteoblast activity and inhibits osteoclast-mediated bone resorption, thereby preserving skeletal integrity and reducing the risk of osteoporosis, particularly in postmenopausal women.

3. Cardiovascular maintenance:ESR1 contributes to vascular homeostasis by modulating endothelial function, promoting vasodilation, and regulating lipid metabolism. It provides protection against atherosclerosis, hypertension, and other cardiovascular pathologies by reducing inflammation and improving vascular responsiveness.

Clinical and physiological significance:Genetic variants and polymorphisms in ESR1 have been associated with differences in hormonal sensitivity and susceptibility to several conditions. Notably, ESR1 variants influence the risk of osteoporosis, cardiovascular disease, and hormone-dependent cancers such as breast and endometrial cancer. Both loss-of-function and regulatory polymorphisms can alter receptor expression or activity, highlighting ESR1’s critical role in systemic estrogen signaling and its impact on human health.