GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE300nnn/GSE300156/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE300156GEOGSEfalseCircadian Disruption Triggers Trophoblast Differentiation Failure via CLOCK-Dependent Chromatin InstabilityPreeclampsia (PE), a life-threatening hypertensive disorder of pregnancy, lacks effective therapies due to poorly understood pathogenesis. 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. Single-cell RNA-seq reveals CLOCK’s selective expression at the onset of differentiation, where its absence locks cells in a stem-like state. Crucially, WNT activation, stabilization of chromatin and melatonin rescues growth defects in CLOCK-deficient trophoblasts, highlighting actionable therapeutic strategies. Our findings establish a unifying mechanism for PE, linking maternal sleep disturbances, placental epigenetic instability, and impaired differentiation. These findings not only advance PE management but also illuminate a universal mechanism by which circadian regulators safeguard chromatin stability across developmental and disease contexts.2026/06/18GSE300156GSM9054607GSM9054606GSM9054605GSM9054604GSM9054603GSM9054602GSM9054601GSM905460016791300156Homo sapiens