Long non-coding RNA profiling of human lymphoid progenitors reveals transcriptional divergence of B cell and T cell lineages
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69239 | GEO | 2015/10/20
SECONDARY ACCESSION(S): PRJNA284950
REPOSITORIES: GEO
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Project description:Studies of adult human hematopoiesis have until now relied on the expression of CD10 to define lymphoid commitment. We report a novel lymphoid-primed population in human bone marrow that is generated from hematopoietic stem cells (HSC) prior to the onset of CD10 expression and B cell commitment, and is identified by high levels of the homing molecule L-selectin (CD62L). CD10-CD62Lhi progenitors have full lymphoid (B/T/NK) potential, and show reduced myeloid and absent erythroid potential. Genome-wide gene expression analysis demonstrates that the CD10-CD62Lhi population represents an intermediate stage of differentiation between CD34+CD38- HSC and CD34+lin-CD10+ progenitors marked by down-regulation of TAL1 and MPL, upregulation of E2A, CD3E and IL2RG expression, and absent B cell commitment or RAG1/2 expression. Immature CD34+CD1a- thymocytes are also CD62Lhi and L-selectin ligands are expressed at the cortico-medullary junction, suggesting a possible role for L-selectin in human thymic homing. These studies identify the earliest stage of lymphoid priming in human bone marrow. Freshly harvested human bone marrow was ficoll purified, enriched for CD34+, and then FACS sorted. It was then sorted into 3 samples CD34+CD38-, CD34+ CD10- CD62L++, and CD34+ CD10+, with 3 independent biological replicates
2012-08-14 | E-GEOD-35685 | biostudies-arrayexpress
Project description:Studies of adult human hematopoiesis have until now relied on the expression of CD10 to define lymphoid commitment. We report a novel lymphoid-primed population in human bone marrow that is generated from hematopoietic stem cells (HSC) prior to the onset of CD10 expression and B cell commitment, and is identified by high levels of the homing molecule L-selectin (CD62L). CD10-CD62Lhi progenitors have full lymphoid (B/T/NK) potential, and show reduced myeloid and absent erythroid potential. Genome-wide gene expression analysis demonstrates that the CD10-CD62Lhi population represents an intermediate stage of differentiation between CD34+CD38- HSC and CD34+lin-CD10+ progenitors marked by down-regulation of TAL1 and MPL, upregulation of E2A, CD3E and IL2RG expression, and absent B cell commitment or RAG1/2 expression. Immature CD34+CD1a- thymocytes are also CD62Lhi and L-selectin ligands are expressed at the cortico-medullary junction, suggesting a possible role for L-selectin in human thymic homing. These studies identify the earliest stage of lymphoid priming in human bone marrow.
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Project description:Natural killer (NK) cells represent one of three lymphoid lineages and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK-cell commitment remain poorly understood Here we described a novel NK-lineage restricted progenitor (NKP) in fetal development, umbilical cord blood and adult bone marrow. We used microarrays to detail the global programme of gene expression genes of this new progenitor. Global gene expression analysis was performed on the NKP, multipotent progenitors LMPP, common lymphoid progenitor candidate and mature NK cells purified from Cord blood CD34+ cells (3-4 replicates, 2 experiments)
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Project description:Single cell studies elucidating the transcriptional continuum underpinning lineage commitment in the human bone marrow (BM) have advanced the understanding of hematopoiesis beyond the classic hierarchical model. However, T-lineage commitment, which occurs in the thymus remains incompletely defined. We mapped single cell transcriptomes spanning post-natal human thymopoiesis including the earliest progenitors. Instead of previously described discrete populations, transcriptional and lineage assay data resolved a continuum of novel cell states within CD34+ thymic progenitor cells. The initial stages of thymopoiesis involve multilineage priming of single cells followed by a gradual transition to T-commitment, a continuum previously undescribed outside the BM. Early progenitors express a hematopoietic stem cell (HSC) like profile but unlike HSC show initiation of T-priming. Species related differences exist in the earliest progenitor cells.
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Project description:The development of all lymphoid lineages relies on a tightly-controlled series of gene expression patterns as development proceeds through a series of progenitors1-8. These gene expression patterns are understood to be controlled by lineage-specifying transcription factors, however these factors often are found to have broad expression patterns and activities across lineages. Given their role in regulating cell-type specific gene expression, noncoding loci are thought be important in the lineage-specific regulation of this complex process6,9-16. To identify transcripts that might mark such loci, we performed transcriptomic analysis in terminally differentiated murine CD4 effector T lymphocytes. Our analysis identified a variety of loci containing dynamically expressed noncoding RNAs and we tested their role in the lymphoid lineage using an in-vivo CRISPR knockout-mouse screen. This approach revealed that a non-coding locus proximal to the haematopoietic transcription factor Ikaros17,18, named Daedalus, exerted control over the earliest fate decisions during lymphoid lineage commitment. Deletion of Daedalus led to a cell-autonomous reduction in bone marrow and thymic lymphoid progenitor populations, phenocopying Ikaros deficient strains. Strikingly, loss of Daedalus resulted in a loss of Ikaros protein expression without impacting total Ikaros transcript levels. Finally, we identify a novel Ikaros regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage specific manner. Daedalus appears to act as a gatekeeper of Ikaros’s broad lineage specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. To our knowledge, these findings represent the first illustration of how a transcription factor with broad lineage expression must work in concert with non-coding elements to orchestrate haematopoietic lineage specification and commitment.
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