Epigenetic signals controlling gene function are fundamental in normal hematopoiesis and alterations in them are the basis for neoplastic transformation in myeloid leukemias. Hematopoietic stem cell identity and lineage commitment are accompanied by chromatin modifications that parallel changes in gene expression. The activity of microRNAs (miRNAs) is also essential in directing hematopoiesis and an alteration of their regulation can lead to leukemic onset. Our research group previously demonstrated that miR-223 has a nuclear function assembling a chromatin remodelling complex on complementary sequences of its post-transcriptional target NFIA gene promoter. NFIA drives erythroid differentiation and its transcriptional silencing by miR-223 induces myeloid differentiation. Evidences indicate that other miRNAs have nuclear functions and can interact with chromatin structure.
The project is aimed to study at whole genome level the role of miR223-DNA interaction in the differentiation program of myeloid cell lines and hematopoietic progenitor cells (HPCs) in the physiological context of hematopoiesis, to further investigate the perturbation of miRNA nuclear activities in leukemia. Indeed, our preliminary ChIP-seq data showed a spread overlap between miR-223 occupancy and H3K4me3 and H3K27me3 marks in the genome of myeloid cells undergoing granulocytic differentiation. We plan to i) define the genomic localization of miR-223 in the context of hematopoiesis ii) study the changes in expression patterns of identified genes transcriptionally targeted by miR-223 in hematopoietic differentiation iii) Evaluate the role of miR-223 (post-)transcriptional targets in HPC fate decisions.
The identification of novel transcriptional pathways and genes epigenetically regulated by nuclear miR-223 may provide the basis for the identification of novel therapeutic targets, modifying the current view of miRNAs in cell differentiation and neoplastic transformation.
This study will define the genomic landscape of the nuclear activity of miR-223 and the epigenetic signatures generated at its binding sites on target genes and physiologic relevance in normal and neoplastic hematopoiesis.
Indeed, the next frontier in hematological and oncological research will be to examine at the molecular level how specific chromatin signatures influence gene expression. Some of these signatures are transient while others, such as those involved in epigenetic silencing of developmentally regulated genes, are more stable and require several cell divisions to be fully implemented or reversed. Overall, the results of our investigation have the potential to modify the current view of miRNAs function in cell differentiation and neoplastic transformation, demonstrating a genome-wide epigenetically-based transcriptional regulatory activity of nuclear miRNAs and, possibly, providing the basis for the identification of novel markers for the development of innovative treatments in leukemia to be extended to other neoplasia.
As a whole, miRNAs direct interaction with DNA represents a driving force for the DNA targeting activity of chromatin modifying proteins. Unraveling of their networks will provide novel targets for diagnosis, prognosis and therapeutic intervention.