TY - JOUR T1 - A regulatory network of microRNAs confers lineage commitment during early developmental trajectories of B and T lymphocytes. JF - Proc Natl Acad Sci U S A Y1 - 2021 A1 - Nikhat, Sameena A1 - Yadavalli, Anurupa D A1 - Prusty, Arpita A1 - Narayan, Priyanka K A1 - Palakodeti, Dasaradhi A1 - Murre, Cornelis A1 - Pongubala, Jagan M R KW - Animals KW - B-Lymphocytes KW - Cell Differentiation KW - Cell Lineage KW - Gene Expression KW - Gene Expression Profiling KW - Gene Regulatory Networks KW - Hematopoietic Stem Cells KW - Mice KW - MicroRNAs KW - Myeloid Cells KW - T-Lymphocytes AB -

The commitment of hematopoietic multipotent progenitors (MPPs) toward a particular lineage involves activation of cell type-specific genes and silencing of genes that promote alternate cell fates. Although the gene expression programs of early-B and early-T lymphocyte development are mutually exclusive, we show that these cell types exhibit significantly correlated microRNA (miRNA) profiles. However, their corresponding miRNA targetomes are distinct and predominated by transcripts associated with natural killer, dendritic cell, and myeloid lineages, suggesting that miRNAs function in a cell-autonomous manner. The combinatorial expression of miRNAs miR-186-5p, miR-128-3p, and miR-330-5p in MPPs significantly attenuates their myeloid differentiation potential due to repression of myeloid-associated transcripts. Depletion of these miRNAs caused a pronounced de-repression of myeloid lineage targets in differentiating early-B and early-T cells, resulting in a mixed-lineage gene expression pattern. De novo motif analysis combined with an assay of promoter activities indicates that B as well as T lineage determinants drive the expression of these miRNAs in lymphoid lineages. Collectively, we present a paradigm that miRNAs are conserved between developing B and T lymphocytes, yet they target distinct sets of promiscuously expressed lineage-inappropriate genes to suppress the alternate cell-fate options. Thus, our studies provide a comprehensive compendium of miRNAs with functional implications for B and T lymphocyte development.

VL - 118 IS - 46 ER -