Epigenetic silencing of the oncogenic miR-17-92 cluster during PU.1-directed macrophage differentiation

The oncogenic cluster miR‐17‐92 encodes seven related microRNAs that regulate cell proliferation, apoptosis and development. Expression of miR‐17‐92 cluster is decreased upon cell differentiation. Here, we report a novel mechanism of the regulation of miR‐17‐92 cluster. Using transgenic PU.1 −/− myeloid progenitors we show that upon macrophage differentiation, the transcription factor PU.1 induces the secondary determinant Egr2 which, in turn, directly represses miR‐17‐92 expression by recruiting histone demethylase Jarid1b leading to histone H3 lysine K4 demethylation within the CpG island at the miR‐17‐92 promoter. Conversely, Egr2 itself is targeted by miR‐17‐92, indicating existence of mutual regulatory relationship between miR‐17‐92 and Egr2. Furthermore, restoring EGR2 levels in primary acute myeloid leukaemia blasts expressing elevated levels of miR‐17‐92 and low levels of PU.1 and EGR2 leads to downregulation of miR‐17‐92 and restored expression of its targets p21CIP1 and BIM. We propose that upon macrophage differentiation PU.1 represses the miR‐17‐92 cluster promoter by an Egr‐2/Jarid1b‐mediated H3K4 demethylation mechanism whose deregulation may contribute to leukaemic states. This study unravels an epigenetic mechanism for the regulation of the oncogenic miRNA cluster 17‐92, involving the master hematopoietic transcription factor PU.1/Egr‐2 and Jarid1b.