A regulatory network of microRNAs confers lineage commitment during early developmental trajectories of B and T lymphocytes.
Sameena NikhatAnurupa D YadavalliArpita PrustyPriyanka K NarayanDasaradhi PalakodetiCornelis MurreJagan M R PongubalaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- cell fate
- single cell
- gene expression
- dendritic cells
- bone marrow
- dna methylation
- high throughput
- genome wide
- acute myeloid leukemia
- cell therapy
- poor prognosis
- transcription factor
- mesenchymal stem cells
- magnetic resonance imaging
- depressive symptoms
- public health
- risk assessment
- peripheral blood
- binding protein
- stem cells
- computed tomography
- bioinformatics analysis
- genome wide identification
- contrast enhanced