Epigenetic signals and microRNAs (miRNAs) are key regulators of gene expression in developmental programs. Their alterations are at the basis of neoplastic transformation. We reported that during granulocytic differentiation of human hematopoietic stem/progenitor cells (HPC), miR-223 locates into the nucleus where it assembles a chromatin remodelling complex, including Polycomb, Argonaute and Dicer proteins, on complementary sequences of its post-transcriptional target NFI-A gene promoter. NFI-A directs erythroid differentiation, its transcriptional silencing by miR-223 induces myeloid differentiation. This evidence suggests that during HPCs lineage fate determination, miRNAs interact with matching sequences on developmentally regulated gene promoters, providing the driving force for the DNA targeting activity of chromatin modifiers. In addition, our preliminary ChIP-seq data showed an overlap between miR-223 occupancy and H3K4me3 and H3K27me3 marks in myeloid cell lines undergoing granulocytic differentiation. Among the genes marked by H3K27me3 and miR-223-Cy5 we found NFIA, according to our previous published data. Major aim of this project is to study how miRNA-DNA interactions impact in the differentiation program of HPCs and myeloid cell lines, in comparison with the corresponding acute myeloid leukemia (AML) blast phenotypes. We plan to address: i) the genes transcriptionally regulated by miR-223 and their DNA and chromatin status; ii) the biological consequences in HPCs fate decision of the expression/silencing of miR-223 and their transcriptional targets, and the efficacy of treatment with chromatin remodelling agents in normal and leukemic cells.
The identification of novel transcriptional pathways and genes epigenetically regulated by miR-223 may provide; i) novel markers for the diagnosis and prognosis of AML; ii) the basis for development of novel targeted therapies; iii) the background for further exploration and validation in other cancer models.
