The function of MORC4 in human trophoblast identity

The placenta is a vital organ that sustains human development in utero. It provides the site of exchange of gases, nutrients, and metabolites between the maternal and foetal bloodstreams. The human placenta contains progenitors that give rise to highly specialized trophoblast cell types, and failures in their differentiation are associated with placental pathologies. Importantly, transcription factors and chromatin modifiers controlling these cell fate decisions are poorly understood. For instance, Morchidia 4 (MORC4) is a chromatin factor expressed in the progenitor cells of the developing placenta; however, its role remains unknown. Here, we propose to determine the molecular function of MORC4 using human trophoblast stem cells (hTSCs) as an in vitro model of the developing placenta. Based on the MORC4 interaction with a chromatin-modifying complex we observed, we hypothesise that this cooperation sustains the progenitor population and ensures balanced placental development. We postulate that MORC4 controls chromatin accessibility and, together with its interacting partners, ensures transcriptional silencing of differentiation genes and prevents their premature activation, which could lead to placental defects. To illuminate how MORC4 regulates the balance between the progenitor and the specialized, differentiated cell populations, we aim to: 1. Identify genes that are bound and regulated by MORC4 in hTSCs. 2. Determine the molecular mechanisms underlying the MORC4 cooperation with the chromatin-modifying protein complex. We propose to use a comprehensive approach by combining mechanistic advances with functional assays to illuminate the role of MORC4 in human placental development. Our findings will not only clarify the function of MORC4 and its interacting partners but may also provide new insights into the molecular aetiology of placental disorders, including foetal growth restriction, miscarriage, and preeclampsia.