CHD8-Dependent Chromatin Licensing Sustains Trophoblast Stem Cell Transcriptional Programs

Functional placentation relies on the precise balance between trophoblast stem cells (TSCs) self-renewal and differentiation, yet how permissive chromatin states are maintained to support trophoblast gene regulatory networks (GRNs) remains poorly understood. Here, we show that CHD8-dependent chromatin licensing is required for human and mouse TSCs maintenance. CHD8 depletion impairs cell-cycle progression and self-renewal and selectively downregulates key stemness-associated genes. In vivo, reduced placental CHD8 expression is associated with recurrent pregnancy loss in humans, and trophoblast-specific deletion of Chd8 in mice disrupts placentation and causes miscarriage. Mechanistically, CHD8 maintains chromatin accessibility that supports the occupancy of key trophoblast transcription factors (TFs) at their target loci and is associated with KMT2A-dependent H3K4me3 deposition at TSC self-renewal genes. Increasing transcription factor abundance or global H3K4me3 levels is insufficient to restore transcription in CHD8-depleted cells, indicating that chromatin accessibility constitutes a dominant regulatory constraint. Together, these findings identify CHD8-dependent chromatin licensing as a critical regulatory layer that sustains TSC transcriptional programs and placental development.