PU.1 controls the expression of long noncoding RNA HOTAIRM1 during granulocytic differentiation

Abstract

BackgroundLong noncoding RNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) has been characterized as a critical factor in all-trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells. However, the essential transcription factor for gene expression of HOTAIRM1 is still unknown.FindingsChromatin immunoprecipitation (ChIP) assays revealed that PU.1 constitutively bound to the regulatory region of HOTAIRM1. Co-expression of PU.1 led to the transactivation of the regulatory region of HOTAIRM1 in a reporter assay. Detailed analysis showed that two PU.1 motifs, which were located around +1100 bp downstream of the transcriptional start site of the HOTAIRM1 promoter, were responsible for the PU.1-dependent transactivation. The induction of HOTAIRM1 by ATRA was dependent on PU.1, and ectopic expression of PU.1 significantly up-regulated HOTAIRM1. Furthermore, low HOTAIRM1 expression was observed in APL cells, which was attributed to the reduced PU.1 expression rather than the repression by PML-RARα via the direct binding.ConclusionPU.1 directly activates the expression of HOTAIRM1 through binding to the regulatory region of HOTAIRM1 during granulocytic differentiation. The reduced PU.1 expression, rather than PML-RARα itself, results in the low expression of HOTAIRM1 in APL cells. Our findings enrich the knowledge on the regulation of lncRNAs and the underlying mechanisms of the abnormal expression of lncRNAs involved in APL.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0274-1) contains supplementary material, which is available to authorized users.

HOTAIRM1 competed endogenously with miR‐148a to regulate DLGAP1 in head and neck tumor cells

“…Recent study indicated that HOTAIRM1 is a tumor suppressor by affecting a series of genes related to cell proliferation in acute myeloid leukemia . Relying on the two PU.1 motifs at the HOTAIRM1 promoter, the increasing expression of PU.1 contributes to the dysregulation of HOTAIRM1 in acute myeloid leukemia cells . Wan et al.…”

“…HOX antisense intergenic RNA myeloid 1 (HOTAIRM1), a long noncoding RNA (lncRNA), was found recently to participate in various tumor metastasis . HOTAIRM1 may act as regulator of gene expression during myelopoiesis which is expressed from HOXA genomic cluster between HOXA1 and HOXA2 . HOTAIRM1 has been demonstrated to play a role in various cancers, including colorectal cancer , adenocarcinoma , breast cancer , and acute myeloid leukemia .…”

Long noncoding RNAs and their epigenetic function in hematological diseases

“…Recently, they also reveal that PU.1 directly activates the expression of HOTAIRM1 through binding to the regulatory region of HOTAIRM1 during granulocytic differentiation. Reduced PU.1 expression, rather than PML‐RARα itself, results in the low expression of HOTAIRM1 in APL cells . Chen et al show that HOTAIRM1 acts as a microRNA sponge in an autophagy pathway that includes miR‐20a/106b, miR‐125b, and their targets ULK1, E2F1, and DRAM2.…”

Long noncoding RNAs: pivotal regulators in acute myeloid leukemia

“…Most recently, we have found that the myeloid differentiation lncRNA HOTAIRM1 is a direct target of PU.1 [40]. The up-regulation of HOTAIRM1 during granulopoiesis depends on PU.1.…”