Poster #084, Cedars Sinai Medical Center
PRC2 Inhibition Remodels Retinoid Regulatory Networks to Promote Caudal Motor Neuron Regionalization in Human iPSC-Derived Motor Neuron Progenitors
Mentors: Ken Ning and Ritchie Ho, PhD
Regional motor neuron identity is established through rostrocaudal HOX gene activation during development, yet how epigenetic repression interfaces with developmental signaling in human cells remains poorly understood. We investigated the role of Polycomb Repressive Complex 2 (PRC2) in human induced pluripotent stem cell (iPSC)-derived motor neuron progenitors from age-matched, sex-balanced healthy donors. Pharmacological inhibition of PRC2 using Valemetostat (VT) induced a robust caudal HOX transcriptional program, demonstrating that PRC2 normally restricts caudal identity. Comparative gene expression, protein, and immunofluorescence analyses further showed that dual inhibition of EZH1/2 enhanced caudal HOX induction and neurite outgrowth without compromising motor neuron progenitor identity, indicating that efficient PRC2 suppression promotes caudal regionalization. Bulk mRNA sequencing identified significant remodeling of the retinoid regulatory network following PRC2 inhibition, including marked upregulation of the retinoic acid (RA) synthesis enzyme ALDH1A2 (RALDH2) together with altered expression of multiple retinoid pathway components. Functional studies further demonstrated a complex interaction between PRC2 inhibition and retinoid signaling, suggesting that PRC2 regulates caudal patterning not only through chromatin remodeling but also through broader reprogramming of retinoid homeostasis. Despite these molecular changes, OLIG2 expression was preserved, indicating that motor neuron progenitor identity was maintained while regional identity was selectively remodeled. Collectively, these findings identify PRC2 as a key epigenetic regulator of human motor neuron regionalization and reveal an unexpected link between PRC2 activity and the retinoid regulatory network.