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TCF7 is a key regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE30068 | GEO | 2012/03/30

SECONDARY ACCESSION(S): PRJNA144003

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.

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TCF7 is a key regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line

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