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Gene expression of human bone marrow granulocytic differentiation stages

ABSTRACT: Long non-coding RNAs (lncRNAs) and miRNAs have emerged as crucial regulators of gene expression and cell fate decisions. Here we present an integrated analysis of the ncRNA-landscape of purified human hematopoietic stem cells (HSCs) and their differentiated progenies, including granulocytes, monocytes, T-cells, NK-cells, B-cells, megakaryocytes and erythroid precursors. For each blood cell population, RNA from 5 healthy donors was hybridized onto three microarray platforms (Arraystar lncRNA V2.0, NCode™-miRNA/-ncRNA), yielding a coverage of more than 40,000 lncRNAs, 25,000 mRNAs and 900 miRNAs on 146 arrays. T-distributed stochastic neighbor embedding (t-SNE) on noncoding genes structured the dataset into groups of samples that matched the input populations, demonstrating their unique lncRNA expression profiles. Self-organizing maps (SOMs) revealed clusters of lncRNAs and mRNAs that were coordinately expressed in HSCs and during lineage commitment. Using a “guilt-by-association” approach we assigned putative functions to lncRNAs regulated during differentiation, which predicted LINC00173 as a novel non-coding regulator of granulopoiesis. We knocked down LINC00173 using two independent shRNA constructs, which resulted in diminished granulocytic in vitro differentiation, myeloid colony-formation and function. Next, we uncovered a strong and highly coordinated upregulation of miRNAs, small nucleolar RNAs (snoRNAs) and lncRNAs within the DLK1-DIO3 locus on chromosome 14 (hsa14) during megakaryocytic maturation. shRNA-mediated knock-down of noncoding members of the locus reduced erythroid colony-formation and megakaryocytic cell proliferation in vitro implicating the functional importance of this ncRNA locus in megakaryopoiesis. This series only contains the RNAseq data obtained from successive stages of human granulocytic differentiation (myeloblasts, promyelocytes, metamyelocytes and neutrophils) which was obtained to validate the differentiation-dependent expression of LINC00173 in human granulopoiesis. To access the microarray data see GSE98633 and GSE98791.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98946 | GEO | 2017/08/21

SECONDARY ACCESSION(S): PRJNA386905

REPOSITORIES: GEO

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Project description:MicroRNA plays a critical role in a wide variety of biological processes and regulate genes associated with different biological processes such as development, proliferation, apoptosis, stress response, and tumourigenesis. Profiling miRNA expression during differentiation of embryonic stem cells will help to understand the regulation pathway of differentiation, which in turn may elucidate disease mechanisms. In human hematopoiesis that requires a tight control of gene expression, lineage-specific transcription factors have long been known to act as key regulators of gene expression in multiple cell-fate decisions that govern cell differentiation. Given the important role of miRNAs in development and differentiation, it would be beneficial to elucidate the role of miRNAs in hematopoiesis for identifying novel drug targets. We undertook the current study of examining the expression of miRNA expression in CD34+ before and after differentiation into erythropoietic, granulopoietic and megakaryocytic cells using Affymetrix V 2.0 miRNA genechips. We identified 388 probesets representing 140 miRNAs, snoRNAs and stemloop RNAs to be significantly altered during lineage specific differentiation of CD34+ cells. Of these differentially expressed miRNAs with functional roles in cellular growth and proliferation, differentiation and apoptosis, 16 downregulated miRNAs were found to overlap between the E, M and G groups, hsa-miR150 was significantly downregulated and hsa-miR 210 and hsa-miR-1260b were found to be uniquely upregulated during granulopoiesis while hsa-miR486 was found to be upregulated during erythropoiesis and downregulated in megakaryopoiesis. Megakaryopoitic differentiation specifically resulted in significant down regulation of many miRNAs such as mir -150, mir -155, mir-15, mir-181, mir-221 that seem to play critical roles in the regulation of B and T cell differentiation . An integrated analysis of the differentially expressed miRNA and mRNA identified specific gene targets that are regulated by the significantly altered micro RNAs during lineage specific hematopoiesis. We believe that this study would enhance our understanding of the role of miRNA in lineage specific gene expression. CD34+ cells were compared to differentiated Erythropoitic, granulopoietic and megakaryopoiteic groups to identify differentially expressed microRNAs Human hematopoietic progenitor cells

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Gene expression of human bone marrow granulocytic differentiation stages

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