Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive.

Authors report that HoxBlinc RNA first specifies Flk1⁺ mesoderm and then promotes hematopoietic differentiation through regulation of hoxb pathways. 

HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes.

Depletion of HoxBlinc by shRNA-mediated knockdown or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxbgenes and other factors regulating cardiac/hematopoietic differentiation.

Reduced hoxbexpression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2–b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1⁺ precursors that undergo hematopoietic differentiation.

Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1⁺ precursors and differentiation of Flk1⁺ cells into hematopoietic lineages.

http://www.cell.com/cell-reports/abstract/S2211-1247(15)01419-9