Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells.
HOTAIRM1 is a long intergenic non-coding RNA encoded in the human HOXA gene cluster, with gene expression highly specific for maturing myeloid cells. Knockdown of HOTAIRM1 in the NB4 acute promyelocytic leukemia cell line retarded all-trans retinoid acid (ATRA)-induced granulocytic differentiation, resulting in a significantly larger population of immature and proliferating cells that maintained cell cycle progression from G1 to S phases. Correspondingly, HOTAIRM1 knockdown resulted in retained expression of many otherwise ATRA-suppressed cell cycle and DNA replication genes, and abated ATRA induction of cell surface leukocyte activation, defense response, and other maturation-related genes. Resistance to ATRA-induced cell cycle arrest at the G1/S phase transition in knockdown cells was accompanied by retained expression of ITGA4 (CD49d) and decreased induction of ITGAX (CD11c). The coupling of cell cycle progression with temporal dynamics in the expression patterns of these integrin genes suggests a regulated switch to control the transit from the proliferative phase to granulocytic maturation. Furthermore, ITGAX was among a small number of genes showing perturbation in transcript levels upon HOTAIRM1 knockdown even without ATRA treatment, suggesting a direct pathway of regulation. These results indicate that HOTAIRM1 provides a regulatory link in myeloid maturation by modulating integrin-controlled cell cycle progression at the gene expression level.
Department of Pediatrics; University of Massachusetts Medical School; Worcester, MA USA.
Xueqing
X
Zhang
Department of Genetics; Yale University; New Haven, CT USA.
Sherman M
SM
Weissman
Department of Pediatrics; University of Massachusetts Medical School; Worcester, MA USA; Department of Cancer Biology; University of Massachusetts Medical School; Worcester, MA USA.
Peter E
PE
Newburger
D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology
D039521:CD11c Antigen; C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D039441:Integrin alpha4; D014212:Tretinoin
HOX cluster; cell cycle; gene expression; granulocyte; integrin; long noncoding RNA; myeloid; myelopoiesis