714 An essential role for CRL complex signaling in epidermal differentiation

Maintenance of skin homeostasis requires meticulous regulation the induction, repression and degradation key signaling factors governing progenitor cell terminal differentiation programs. Deregulation these pathways is a hallmark barrier disruption often manifested in disease. Timed controlled orchestration networks involves ubiquitin ubiquitin-like proteins, as abnormal targeted or post-translational modifications are evidenced conditions harboring mutations including xeroderma pigmentosum, autosomal recessive congenital ichthyosis, cancer, dermatomyositis. By combining CRISPR genetic screen genes encoding proteins with single-cell RNA-sequencing primary, differentiated keratinocytes, we demonstrate cluster 26 marked impact on epidermal differentiation. Through analysis individual gene targets, signatures state affected by perturbations, identify new functions for regulating proliferation. We specific receptor-adaptor-substrates tethered Cullin-RING E3 ligase complexes (CRLs), having dramatic effect pathways. This adaptor-receptor-substrate CRLs determines differentiation, which has implications therapeutic interventions this pathway.