Organisms regulate cell size and shape to function efficiently. Aberrant cell morphogenesis is commonly associated with disease, yet gene-regulatory mechanisms remain unknown. CISTR-ACT was the first lncRNA involved in inter- chromosomal proximities and Mendelian disease, and it is associated with mean corpuscular volume (red blood cell size). Here, functional dissection of CISTR-ACT ’s DNA- and RNA-encoded mechanisms by in vitro and in vivo perturbations reveals that CISTR-ACT regulates cell size across cell types and species. CISTR-ACT ’s locus is embedded in a stable inter- chromosomal environment which contains cell size genes that are regulated by CISTR-ACT in trans. CISTR-ACT ’s RNA also has function and directly interacts with transcription factor FOSL2 to guide its regulation of cell morphogenesis and cell-cell adhesion genes. In the absence of CISTR-ACT , the FOSL2-chromatin binding is perturbed. Our study exemplifies how a functionally conserved lncRNA regulates cell size with multiple modes of action and ultimately contributes to clinically relevant phenotypes.
