Structurally conserved primate lncRNAs are transiently expressed during human cortical differentiation and influence cell type specific genes

Andrew R. Field, Frank M.J. Jacobs, Ian T. Fiddes, Alex P.R. Phillips, Andrea M. Reyes-Ortiz, Erin LaMontagne, Lila Whitehead, Vincent Meng, Jimi L. Rosenkrantz, Maximillian Haeussler, Sol Katzman, Sofie R. Salama, David Haussler


The cerebral cortex has expanded in size and complexity in primates, yet the molecular innovations that enabled primate-specific brain attributes remain obscure. We generated cortical organoids from human, chimpanzee, orangutan, and rhesus pluripotent stem cells and sequenced their transcriptomes at weekly time points for comparative analysis. We used transcript structure and expression conservation to discover gene regulatory long non-coding RNAs (lncRNAs). Of 2,975 human, multi- exonic lncRNAs, 2,472 were structurally conserved in at least one other species and 920 conserved in all. 386 human lncRNAs were transiently expressed (TrEx) and many were also TrEx in great apes (46%) and rhesus (31%). Many TrEx are expressed in specific cell types by scRNA-seq. Four TrEx lncRNAs selected based on cell type specificity, gene structure, and expression pattern conservation were ectopically expressed in HEK293 cells by CRISPRa. All induced trans gene expression changes consistent with neural gene regulatory activity.

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stem cells; induced pluripotent stem cells; brain development; human evolution; neurogenesis; neural development; lncRNA; primate evolution; great ape iPSC; scRNA-Seq; RNA-seq