LncRNA Spehd regulates hematopoietic stem cells and progenitors and is required for multilineage differentiation

Long non-coding RNAs (lncRNAs) show patterns of tissue- and cell-type-specific expression that are very similar to those of protein coding genes and consequently have the potential to control stem and progenitor cell fate decisions along a differentiation trajectory. To understand the roles that lncRNAs might play in hematopoiesis, we selected a subset of mouse lncRNAs with potentially relevant expression patterns and refined our candidate list using evidence of conserved expression in human blood lineages. For each candidate, we assessed its possible role in hematopoietic differentiation in vivo using competitive transplantation. Our studies identified two lncRNAs that were required for hematopoiesis. One of these, Spehd, showed defective multi-lineage differentiation, and its silencing yielded common myeloid progenitors deficient in their oxidative phosphorylation pathway. This effort not only suggests that lncRNAs can contribute to differentiation decisions during hematopoiesis but also provides a path toward the identification of functional lncRNAs in other differentiation hierarchies. Overall design: Transcriptome analysis was performed on shRNA-expressing sorted bone marrow progenitors cells (LSK, CMP). The animals had been transplanted with hematopoietic stem cells transduced with inducible shRNA vectors against lncRNA12928/Spehd or control knockdown , they were allowed to reconstitute for 10 weeks and administered doxycycline-containing food for 6 days. The objective was to identify transcriptional changes upon lncRNA loss.