Active chromatin marks and up-regulation of FOXC1 in uterine epithelial cells demarcate the onset of reproductive decline in aging females.

Advanced maternal age increases the risk of pregnancy complications due, in part, to changes in the uterine environment. Here, we show that uterine aging in mice is associated with a progressive increase in transcriptional variation, accompanied by a notable accumulation of activating histone marks at multiple genomic loci. Importantly, the transcriptional signatures of uterine aging differ substantially from senescence markers associated with organismal aging. We demonstrate that maternal age-induced effects largely originate in the epithelial compartment and entail a dramatic up-regulation of the pioneer transcription factor FOXC1, combined with a hyper-enrichment for H3K27ac and H3K4me3 across the locus. FOXC1 over-expression in human endometrial epithelial cells causes profound transcriptomic shifts and increased proliferation, recapitulating the aging phenotype. Using endometrial epithelial organoids of young and aged mice, we find that aging hallmarks including Foxc1 up-regulation and epithelial H3K27ac hyper-enrichment are conserved in vitro. Recapitulating the epithelial hyperplasia phenotype seen in vivo, endometrial epithelial organoids from aged mice are larger and mis-express key factors, such as SOX9, critical for uterine gland maturity and function. Collectively, our data highlight the susceptibility of uterine epithelial cells to early-onset aging, demarcated by an increase in activating epigenetic marks that converge on the mis-regulation of FOXC1.