Deciphering the regulatory role of micro RNAs during early developmental stages of B and T lymphocytes

Abstract

newline Commitment of multipotent hematopoietic progenitors towards a particular lineage newlineinvolves activation of cell type-specific genes as well as silencing of genes that newlinepromote alternate cell-fates. The transcription factors (TFs) that drive multipotent newlineprogenitors towards B and T lineages have been extensively studied over the past newlinetwo decades; however, the role played by microRNAs expressed during B and T newlinecell-fate commitment, remains less explored. Despite the mutually exclusive gene newlineexpression programs regulating early B- and T-lymphocyte development, we show newlinethat Early-B and Early-T cells exhibit significantly correlated microRNA profiles. newlineInterestingly, profiling of Argonaute2-associated mRNAs revealed that miRNAtargetomes of Early-B and Early-T cells are quite distinct, and predominated by newlinetranscripts that are closely associated with Natural Killer cell (NK), Dendritic Cell newline(DC) and Myeloid lineages. We demonstrate that combinatorial expression of newlinemultiple lymphocyte microRNAs - miR-186-5p, miR-128-3p and miR-330-5p in newlineEbf1-/- progenitors, significantly attenuates their myeloid differentiation capacity newlinedue to repression of myeloid-associated transcripts. Correspondingly, knockdown newlineof these miRNAs during early B and T cell development resulted in de-repression newlineof their myeloid-associated targets. Furthermore, B and T lineage-specific TFs newlinepotentially drive the expression of shared miRNAs in the respective cell-types. newlineCollectively, using genome-wide and molecular analyses, this work demonstrates newlinethat microRNAs function as integrated components of gene regulatory networks newlinethat dictate lymphoid cell-fate commitment.