<i>Dlk1-Dio3</i> locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity.

Abstract

The mammalian imprinted <i>Dlk1-Dio3</i> locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including <i>Meg3</i> (i.e., <i>Gtl2</i>) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the <i>Dlk1-Dio3</i> locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, <i>Meg3</i> and other <i>Dlk1-Dio3</i> locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal <i>Hox</i> genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the <i>Dlk1-Dio3</i> locus, particularly <i>Meg3</i>, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating <i>Hox</i> genes.