Promoter hijacking by primate LINC00473 disrupts an ancestral CREB-PDE10A feedback loop

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ABSTRACT Thousands of human long noncoding RNAs (lncRNAs) evolved in primates, although much remains unknown about how these lncRNAs shaped human gene regulatory networks. The primate-specific lncRNA gene LINC00473 has a CREB-inducible promoter that is conserved beyond primates and the gene is located upstream of PDE10A, which encodes an inhibitor of CREB. To gain insight into the regulatory consequences of LINC00473 acquisition, we tested the cellular function of the conserved mouse promoter. We found that the homologous mouse promoter is induced by CREB and regulates the downstream Pde10a gene in C2C12 myoblast-like cells and neurons. Activation of this promoter by CRISPRa increased Pde10a transcript and protein levels, and proteomics revealed that elevated Pde10a promoted C2C12 differentiation at the expense of proliferation. Activation of Pde10a by CRISPRa also impaired CREB-dependent gene expression, suggesting that the mouse homolog of the LINC00473 promoter drives a CREB-Pde10a feedback loop. In contrast to the mouse homolog, human LINC00473 promoter activation by CRISPRa increased LINC00473 expression with either no change in PDE10A or delayed induction compared to mice. Our findings suggest that the newly evolved LINC00473 gene hijacked an ancestral CREB-inducible Pde10a promoter, thereby disrupting a negative feedback loop that may otherwise constrain CREB-dependent gene expression. GRAPHICAL ABSTRACT

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