LncRNA CISTR-ACT regulates cell size in human and mouse by guiding FOSL2

Abstract

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.