A bifunctional, moonlighting RNA coordinates pathways to regulate human embryonic development [RNA-seq]

Early embryogenesis and cellular differentiation require complex choreography between nuclear and cytoplasmic pathways. Through integrative analysis and a short open reading frame functional screen, sORF-seq, we identified lncPRESS1, a bifunctional long-non-coding RNA that also encodes a microprotein. In the nucleus, lncPRESS1 binds BRG1 to regulate chromatin remodeling and modulate the expression of pluripotency and differentiation genes. In the cytoplasm, lncPRESS1 is translated into a microprotein that binds to IFT57, regulating ciliogenesis and SHH signaling pathways to control lineage commitment. Together, these results reveal a novel mechanism where the dual functions of lncPRESS1 simultaneously coordinate chromatin remodeling and signaling pathways. This coordination co-regulates the initial developmental decisions specifying neuroectoderm and mesoderm fates during human embryonic development, underscoring the underappreciated complexity of multifunctional RNAs.