Lineage selection and self-renewal in a murine multipotent hematopoietic precursor
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158006 | GEO | 2023/10/28
REPOSITORIES: GEO
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Project description:The mammalian blood system is a hierarchically structured tissue. Hematopoietic stem cells (HSC) reside at the top of this hierarchy and the HSC-derived progenitor cells (HPC) have capacities for both differentiation and self-renewal. Systematic study of the regulatory mechanisms of HSC self-renewal and differentiation is fundamentally important for understanding hematopoiesis and for manipulating HSCs for therapeutic purposes. Herein, the mechanisms regulating HSC biology were studied on a genome-wide scale by integrating epigenomic, transcriptomic, proteomic, and protein-protein interaction data. Previously, we have characterized gene expression and identified important transcription factors (TFs) regulating the switch between self-renewal and differentiation in a multipotent hematopoietic progenitor cell line, EML (Erythroid, Myeloid, and Lymphoid). In the present study, we report binding maps for three additional TFs (SOX4, STAT3, and GABP) that were developed by chromatin immunoprecipitation (ChIP)-Sequencing. Assay for Transposase Accessible Chromatin (ATAC)-Sequencing was applied to globally identify the open chromatin regions associated with TF binding in the self-renewing subpopulation lin-CD34+.Mass spectrometry (MS) was also used to identify proteins and assess differences in their relative abundances. We found that MAPK (Mitogen-activated protein kinase) pathway and JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway components were highly enriched among the binding targets of these TFs in CD34+ cells, and that the TGF-β/SMAD signaling pathway comprised a sub-network of molecules that were differentially expressed between the lin-CD34+ and partially differentiated lin-CD34- cellular states. The present study integrates regulatory information at multiple levels to paint for the first time a more comprehensive picture of the mechanisms underlying the decision between HPC self-renewal and differentiation. We anticipate that this work will provide valuable clues for understanding the molecular switch that controls cell fate decisions between self-renewal or differentiation and blood formation.
2018-06-04 | GSE100689 | GEO
Project description:A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34- cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a key regulator in this self-renewal/differentiation switch, and it operates in the absence of canonical Wnt signaling. We found that TCF7 is the most downregulated transcription factor when CD34+ cells switch into CD34- cells using RNA-Seq. We subsequently identified the target genes bound by TCF7 using ChIP-Seq. We show that TCF7 binds to Runx1 (Aml1) promoter region, and RUNX1 and TCF7 co-regulate. Gene Set Enrichment Analysis suggests that TCF7 primarily acts as a positive regulator of genes preferentially expressed in CD34+ cells. Consistent with this possibility, knocking-down TCF7 represses many up-regulated genes in Lin-CD34+ cells. Finally a network of up-regulated transcription factors of CD34+ cells which defines the self-renewing state was constructed. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems. Examining the transcription factor binding targets of TCF7 and RUNX1.
2012-03-29 | E-GEOD-31221 | biostudies-arrayexpress
Project description:A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34- cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a key regulator in this self-renewal/differentiation switch, and it operates in the absence of canonical Wnt signaling. We found that TCF7 is the most downregulated transcription factor when CD34+ cells switch into CD34- cells using RNA-Seq. We subsequently identified the target genes bound by TCF7 using ChIP-Seq. We show that TCF7 binds to Runx1 (Aml1) promoter region, and RUNX1 and TCF7 co-regulate. Gene Set Enrichment Analysis suggests that TCF7 primarily acts as a positive regulator of genes preferentially expressed in CD34+ cells. Consistent with this possibility, knocking-down TCF7 represses many up-regulated genes in Lin-CD34+ cells. Finally a network of up-regulated transcription factors of CD34+ cells which defines the self-renewing state was constructed. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems. The gene expression changes when TCF7 is knocked-down by shRNA in Lin-SCA+CD34+ cells were identified by microarray analysis of one control and two experimental samples.
2012-03-29 | E-GEOD-30068 | biostudies-arrayexpress
Project description:A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34- cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a key regulator in this self-renewal/differentiation switch, and it operates in the absence of canonical Wnt signaling. We found that TCF7 is the most downregulated transcription factor when CD34+ cells switch into CD34- cells using RNA-Seq. We subsequently identified the target genes bound by TCF7 using ChIP-Seq. We show that TCF7 binds to Runx1 (Aml1) promoter region, and RUNX1 and TCF7 co-regulate. Gene Set Enrichment Analysis suggests that TCF7 primarily acts as a positive regulator of genes preferentially expressed in CD34+ cells. Consistent with this possibility, knocking-down TCF7 represses many up-regulated genes in Lin-CD34+ cells. Finally a network of up-regulated transcription factors of CD34+ cells which defines the self-renewing state was constructed. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems.
2012-03-30 | GSE31221 | GEO
Project description:A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor cells as a primary model. EML cells give rise to a mixture of self-renewing Lin-SCA+CD34+ cells and partially differentiated non-renewing Lin-SCA-CD34- cells in a cell autonomous fashion. We identified and validated the HMG box protein TCF7 as a key regulator in this self-renewal/differentiation switch, and it operates in the absence of canonical Wnt signaling. We found that TCF7 is the most downregulated transcription factor when CD34+ cells switch into CD34- cells using RNA-Seq. We subsequently identified the target genes bound by TCF7 using ChIP-Seq. We show that TCF7 binds to Runx1 (Aml1) promoter region, and RUNX1 and TCF7 co-regulate. Gene Set Enrichment Analysis suggests that TCF7 primarily acts as a positive regulator of genes preferentially expressed in CD34+ cells. Consistent with this possibility, knocking-down TCF7 represses many up-regulated genes in Lin-CD34+ cells. Finally a network of up-regulated transcription factors of CD34+ cells which defines the self-renewing state was constructed. These studies in EML cells demonstrate fundamental cell-intrinsic properties of the switch between self-renewal and differentiation, and yield valuable insights for manipulating HSCs and other differentiating systems.
2012-03-30 | GSE30068 | GEO
Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation. ChIP-Seq was accomplished by immunoprecipitating endogenous RNA PolII, c-Myc and Sox2
2015-02-18 | E-GEOD-62513 | biostudies-arrayexpress
Project description:Our study disclosed previously unrecognized heterogeneity in fetal liver (FL) hematopoietic stem cells (HSC), highlighting biosynthetic dormancy as a key to symmetric self-renewal of engraftable HSC and supports recent studies demonstrating distinct developmental origins for multipotent progenitors and HSC in definitive hematopoiesis.
2023-05-24 | GSE233031 | GEO
Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation. Progenitor cells from embryonic inner ear that form otospheres were infected with a c-Myc retrovirus to promote self-renewal
2015-02-18 | E-GEOD-62512 | biostudies-arrayexpress
Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation.
2015-02-18 | GSE62513 | GEO
Project description:An immortalized multipotent otic progenitor (iMOP) cell was generated by transient expression of c-Myc in Sox2-expressing otic progenitor cells. The procedure activated endogenous c-Myc expression in the cells and amplified existing Sox2-dependent transcripts to promote self-renewal. Downregulation of c-Myc expression following growth factor withdrawal resulted in a molecular switch from self-renewal to otic differentiation.
2015-02-18 | GSE62512 | GEO