Transcriptional diversity during lineage commitment of human blood progenitors

Abstract

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identify extensive cell-type specific expression changes: 6,711 genes and 10,724 transcripts, enriched in non-protein coding elements at early stages of differentiation. In addition, we discovered 7,881 novel splice junctions and 2,301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrate experimentally cell specific isoform usage, identifying NFIB as a regulator of megakaryocyte maturation -the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

“…In contrast, GFI1B affects primarily the erythroid and MK lineages with importance given to differential splicing and the production of an alternatively spliced shorter form lacking exon 4. Nonetheless it is the longer form that is essential for MK development, a finding confirmed by expression studies in a zebrafish model [26]. The full length GFI1B protein contains a short N-terminal SNAG (Snail-GFI1B) repressor domain acting on target genes by forming complexes with protein cofactors including GATA1 and acting through the recruitment of histone-modifying enzymes.…”

“…Cartoon of the GFI1B gene and GFI1B protein that shows genetic variants identified in patients with inherited defects of platelet production and function. The gene, located on chromosome 9, was originally said to consist of 11 exons although only 6 code for the GFI1B protein and following Chen et al [26] these are labeled 1 through 6 on the Figure. The N-terminal end starts with a short SNAG (Snail-Gfi1b) repressor domain followed by an intermediate domain and six zinc finger (ZNF) domains involved in DNA binding. We show the full-length GFI1B protein, a shorter splice form lacking ZNF2 and parts of ZNF1 and 3 may also be found in hematopoietic tissue.…”

“…Genetic variants of GFI1B were quite recently featured in a detailed report on transcriptional diversity during lineage commitment of human blood progenitors [26]. Included were results for exome sequencing performed by the BRIDGE consortium for over 500 cases with non-genotyped inherited defects of platelet production and/or function.…”

“…GFI1B can influence expression of surface adhesion molecules on blood cells and is a key element in the reciprocal regulation of blood cell lineages by regulator of G-protein signaling 18 (RGS18), a GTPase-activating protein that acts through mitogen-activated protein kinase family members [23,31]. The findings of Chen et al [26] and the results from Gfi1b knockout mouse models therefore point to a more general role of GFI1B in MK development than simply acting as a gene responsible for a-granule biogenesis.…”

Identification and characterization of an injury-induced skeletal progenitor

“…Injury, infection, and aging have been shown to induce lineage skewing of hematopoietic stem cell (HSC) progeny (7)(8)(9). It is now known that HSCs are a diverse population of cells, including HSCs with lineage biases (10), that could model heterogeneity in other tissue stem cells (1,(11)(12)(13). Thus, we propose that fracture activates a distinct subset of skeletal stem and progenitor cells that mediate tissue regeneration and repair.…”