Circadian Disruption Triggers Trophoblast Differentiation Failure via CLOCK-Dependent Chromatin Instability

While maternal sleep disturbances are epidemiologically linked to PE, the molecular mechanisms remain elusive. Here, we identify the circadian regulator CLOCK as a master epigenetic stabilizer critical for placental development, whose dysfunction drives PE pathogenesis.

Through multi-omics analyses of human PE placentae and mechanistic studies in murine models, we demonstrate that maternal sleep deprivation downregulates placental CLOCK, recapitulating PE phenotypes, and CLOCK deficiency triggers global chromatin decompression, suppresses WNT/β-catenin signaling, and arrests trophoblast differentiation. Mechanistically, CLOCK interacts with heterochromatin proteins HP1α and H1.0 to maintain nucleosome stability, while its loss increases chromatin accessibility and suppresses WNT/β-catenin signaling.