Hematopoietic Fingerprints: an expression database of stem cells and their progeny
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE6506 | GEO | 2007/11/21
SECONDARY ACCESSION(S): PRJNA98681
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells (HSC) continuously regenerate a complete hematologic and immune system. Very few genes that regulate this process have yet been identified. In order to identify factors governing differentiation, we have compared the transcriptome of highly purified HSC with their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naïve T-cells, and B-cells. Chromosomal analysis revealed that HSC were more transcriptionally active than other cell types across most chromosomes. Each lineage expressed ~100 to 400 genes uniquely, including many previously uncharacterized genes. Overexpression of two fingerprint genes resulted in a significant bias in differentiation indicating a role in cell fate determination, demonstrating the utility of these data for modulation of specific cell types. Experiment Overall Design: Goal - Expression profiling of hematopoietic cells Experiment Overall Design: Description - Biological replicates of 10 hematopoietic cell types from female C57Bl/6 mice were purified for microarray analysis Experiment Overall Design: Experimental Factors: wild-type female C57Bl/6 CD45.1 Mus musculus Experiment Overall Design: Experimental Design: 25,000- 50,000 cells were FACS sorted, mRNA was purified by RNAqueous (Ambion), DNAse treated with DNAse1, phenol:chloroform:isoamyl alcohol extracted, and amplified through two rounds of in vitro transcription using MessageAmp (Ambion). Second round was biotinylated with bio-CTP and bio-UTP. Experiment Overall Design: Microarrays: Oligonucleotide, Affymetrix, Moe430 v 2.0 Experiment Overall Design: QC: Biological replicates, correlation coefficient > .95; scale factor <10; 5'/3' ratio < 20
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Project description:Hematopoietic stem cells (HSCs) continuously regenerate the hematologic system, yet few genes regulating this process have been defined. To identify candidate factors involved in differentiation and self-renewal, we have generated an expression database of hematopoietic stem cells and their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naive T cells, and B cells. Bioinformatic analysis revealed HSCs were more transcriptionally active than their progeny and shared a common activation mechanism with T cells. Each cell type also displayed unique biases in the regulation of particular genetic pathways, with Wnt signaling particularly enhanced in HSCs. We identified approximately 100-400 genes uniquely expressed in each cell type, termed lineage "fingerprints." In overexpression studies, two of these genes, Zfp 105 from the NK cell lineage, and Ets2 from the monocyte lineage, were able to significantly influence differentiation toward their respective lineages, demonstrating the utility of the fingerprints for identifying genes that regulate differentiation.
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Project description:Hematopoietic stem cells (HSC) possess life-long self-renewal activity and generate a series of multipotent progenitors that differentiate into lineage-committed progenitors and subsequently mature cells. Recently, functionally distinct stem and progenitor cell types have been identified, however, a systems-wide understanding of the underlying gene regulation is lacking. Here, we present the global transcriptome of ex vivo isolated mouse multipotent hematopoietic stem cells (HSC) and multipotent progenitor cells (MPP1-MPP4) as revealed by next-generation sequencing (RNA-seq). A related high-throughput study with DNA methylome data was also conducted, with data deposited at NCBI Gene Expression Omnibus, under accession GSE52709 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52709 ). An imported copy of the methylome data set can also be found at ArrayExpress: http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-52709.
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Project description:Hematopoiesis is a well-established model system to study molecular mechanisms of lineage-specific differentiation. Key transcription factors (TFs), such as PU.1, NF-E2 and GATA1 are implicated in crucial aspects of distinct hematopoietic lineages. How TFs collaborate with histone modificatons and how they affect the chromatin status remains to be elucidated. Chromatin-Immunoprecipitation followed by next-generation sequencing (ChIP-seq) has been proven to be an excellent tool to study chromatin modifications genome-wide. In this study, ChIP-seq was used to investigate the H3K4me2 landscape at enhancers during hematopoietic differentiation, starting from the hematopoietic stem cell (HSC) up to the fully differentiated erythrocyte, megakaryocyte or granulocyte. Although cell morphology and gene expression profiles differ extensively in committed erythrocytes, megakaryocytes and granulocytes, the genomic landscape of H3K4me2 is surprisingly alike across the three cell types. Granulocytes, in particular, seem to display an ‘erythocyte-like’ chromatin pattern. Similar results were observed for another chromatin mark, H3K27ac. Unexpectedly, the common progenitors of erythrocytes and granulocytes do not display a similar chromatin pattern, excluding the idea that the H3K4me2 mark is placed early on during differentiation. These results also suggest that the chromatin state is probably not the determining factor for lineage differentiation, but that rather lineage specific TF binding is important. In agreement with this, mature megakaryocytes loose the H3K4me2 mark surrounding erythrocyte-specific genes. This might be explained because megakaryocytes and erythrocytes both express the lineage specific TFs GATA1 and NF-E2. Altogether, we show that committed granulocytes and erythrocytes display similar H3K4me2 and H3K27ac patterns, and that those marks alone cannot predict which genes will be expressed eventually.
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