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A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [expression]

ABSTRACT: Hematopoietic stem cells and multipotent progenitors (MPPs) commitment can be tuned in response to an infection so that their differentiation is biased toward myeloid cells. Here we find that Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, represses a cohort of myeloid genes and activates those linked to lymphoid function. Bach2 repressed both Cebpb and its target Csf1r, encoding C/EBPβ and macrophage colony-stimulating factor receptor (M-CSFr), respectively, whereas C/EBPβ repressed Bach2 and activated Csf1r. Bach2 and C/EBPβ further bound to overlapping regulatory regions at their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression and antagonistic, feed-forward myeloid gene regulations. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. The Bach2-C/EBPβ GRN pathway thus tunes MPP commitment to myeloid and lymphoid lineages under both normal conditions and after infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE80954 | GEO | 2017/03/07

SECONDARY ACCESSION(S): PRJNA320135

REPOSITORIES: GEO

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Project description:To characterize gene expression changes in AML induced by CNTRL-FGFR1, we used RNA-seq analysis of sorted Mac+Gr1+B220+ AML cells (n = 2) from the SP and BM of leukemic mice, as well as sorted Mac+Gr1+ myeloid cells (n=3) from normal mice. Methods: cDNA libraries were generated using the Illumina TruSeq RNA Sample Preparation kit following the manufacturer’s instructions. The quality of the resulting cDNA libraries were assessed using a Bioanalyzer DNA 1000 chip (Agilent) and quantified by quantitative PCR (Bio-Rad). The cDNA libraries were sequenced using paired end Illumina Hiseq2000 protocols (50 cycles). The Illumina sequencing pipeline version 1.8 was employed for transferring raw images to base calls, generating sequence reads, and de-multiplexing the reads. The generated FASTQ files were imported to CLC Genomics Workbench and aligned to the mouse genome, NCBI37/mm9. The transcript expression levels were determined in terms of number of reads per kilobase per million (RPKM) and compared between sorted normal myeloid (Gr1+Mac1+) cells and sorted leukemic myeloid cells. Results: The result showed a remarkable difference between normal (Gr1+Mac1+) and leukemic (Mac+Gr1+B220+) myeloid cells. Gene Set Enrichment Analysis and leading-edge analysis suggested that Mac+Gr1+B220+ cells have the potential to differentiate into either myeloid or T-cell, but not a B-cell, lineages. Quantitative RT-PCR analysis of lineage-specific genes showed increased expression of Flt3, Gfi1, and Kit related to early myeloid-lineage commitment, while genes related to myeloid differentiation, Irf8, Klf4, Csf1r, Myc, and Spi1 were decreased compared with normal myeloid cells. Quantitative RT-PCR also confirmed that the Cd3e and Lmo2 T-cell specific genes were markedly increased in AML cells. Conclusions: We demonstrate that the CNTRL-FGFR1 fusion kinase induces bi-lineage myeloid and T-lymphoid disease in model mice. Genetic and molecular analyses in these models demonstrated that multiple signaling pathways, specifically related to myeloid and T-lymphoid lineages, were altered in neoplasms, which underscores the importance of developing therapies that target all of these signaling pathways to eradicate the leukemia-initiating-cells RNA-seq analysis of sorted Mac+Gr1+B220+ AML cells (n = 2) from the SP and BM of leukemic mice, as well as sorted Mac+Gr1+ myeloid cells (n=3) from normal mice.

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A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [expression]

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