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Site-specific phosphorylation of ERα determines sex-dependent metabolic, reproductive, and body compositional phenotypes in mice

ABSTRACT: Estrogen receptor alpha (ERα) phosphorylation modulates receptor activity and downstream signaling. Previous studies identified human phosphorylation sites, serine-167 (S167) and serine-212 (S212) as critical regulators of ERα-mediated gene expression. Serine(S) to alanine(A) phospho knock-in mouse models of the corresponding murine sites, S171 and S216, were generated to assess physiological impact. Compared to WT mice, ERα protein levels in tissues were altered in a sex- and phosphorylation site-dependent manner. S216A males exhibited reduced adipose and increased lean mass. S216A females exhibited decreased femur bone density whereas S171A females exhibited increased bone density. S216A females were subfertile with fewer pups/litter. Single-cell and spatial transcriptomics revealed markedly altered E2-regulated uterine gene expression in both models. S216A mice exhibited reduced plasma metabolites in several key metabolic pathways. This study identifies critical roles for site-specific ERα phosphorylation in modulating receptor level/activity and gene expression that has profound impact on murine body composition, fertility, and metabolism.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE291308 | GEO | 2025/05/01

REPOSITORIES: GEO

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Site-specific phosphorylation of ERα determines sex-dependent metabolic, reproductive, and body compositional phenotypes in mice

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