Unknown,Transcriptomics,Genomics,Proteomics

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Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

ABSTRACT: Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors. Genome-wide chromatin occupancy using ChIP-seq on 4 transcription factors (GATA1, GATA2, TAL1, and FLII) and three histone marks (H3K4me1, H3K4me3, and H3K27me3) in lineage-commited primary erythoblasts (ERY) and primary cultured megakaryocytes (MEG).

ORGANISM(S): Mus musculus

SUBMITTER: ENCODE DCC

PROVIDER: E-GEOD-51337 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis.

Pimkin Maxim M Kossenkov Andrew V AV Mishra Tejaswini T Morrissey Christapher S CS Wu Weisheng W Keller Cheryl A CA Blobel Gerd A GA Lee Dongwon D Beer Michael A MA Hardison Ross C RC Weiss Mitchell J MJ

Genome research 20141015 12

Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fet ...[more]

PMID: 25319996

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Project description:MicroRNAs are small non-coding RNAs that regulate cellular development by interfering with mRNA stability and translation. We defined the kinetics of global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were upregulated and 81 were downregulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were upregulated most strongly in megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly upregulated during mouse and human megakaryopoiesis, but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously. Exiqon locked nucleic acid (LNA) microarrays were used to compare microRNA expression in starting populations (ter 119- progenitors) and purified megakaryocytes. Day13.5-14.5 murine fetal livers (strain CD1) were depleted of erythroid cells and cultured with thrombopoietin to generate megakaryocytes. Each total RNA sample (0.5 Î¼g per reaction) was labeled with Hy3 and Hy5 dyes using the Exiqon Power Labeling Kit and automated microarray hybridizations and washes were performed on a Tecan HS4800 station with 20 hr hybridization at 56ÂºC. Dye-swap pairs of three replicate experiments comparing Ter119- fetal liver cells vs. BSA-purified megakaryocytes were co-hybridized to six arrays. The geometric average of the 532 and 635 measurements after normalization was determined for each sample.

Dataset Information

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis

Publications

Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis.

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