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Haematologica 2019 Volume 104(5):894-906
Hematopoiesis
Long noncoding RNAs of single hematopoietic stem and progenitor cells in healthy and dysplastic human bone marrow
Zhijie Wu,1* Shouguo Gao,1* Xin Zhao,1 Jinguo Chen,2 Keyvan Keyvanfar,1 Xingmin Feng,1 Sachiko Kajigaya1 and Neal S. Young1
1Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health and 2Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD, USA
*ZW and SG contributed equally to this work.
ABSTRACT
Long noncoding RNAs (lncRNAs) are regulators of cell differentiation and development. The lncRNA transcriptome in human hematopoi- etic stem and progenitor cells is not comprehensively defined. We investigated lncRNAs in 979 human bone marrow-derived CD34+ cells by single cell RNA sequencing followed by de novo transcriptome reconstruc- tion. We identified 3,173 lncRNAs in total, among which 2,365 were pre- viously unknown, and we characterized lncRNA stem, differentiation, and maturation signatures. lncRNA expression exhibited high cell-to-cell vari- ation, which was only apparent in single cell analysis. lncRNA expression followed a lineage-specific and highly dynamic pattern during early hematopoiesis. lncRNAs in hematopoietic cells closely correlated with protein-coding genes of known functions in the regulation of hematopoiesis and cell fate decisions, and the potential regulatory roles of lncRNAs in hematopoiesis were imputed by projection from protein-cod- ing genes with a “guilt-by-association” approach. We characterized lncRNAs preferentially expressed in hematopoietic stem cells and in vari- ous downstream differentiated lineage progenitors. We also profiled lncRNA expression in single cells from patients with myelodysplastic syn- dromes and in aneuploid cells in particular. Our study provides a global view of lncRNAs in human hematopoietic stem and progenitor cells. We observed a highly ordered pattern of lncRNA expression and participation in regulation of early hematopoiesis, and coordinate aberrant messenger RNA and lncRNA transcriptomes in dysplastic hematopoiesis. (Registered at clinicaltrials.gov with identifiers: 00001620, 00001397)
Introduction
Long noncoding RNAs (lncRNAs), which are defined as a subclass of noncoding RNAs, are longer than 200 nucleotides and lack protein coding capacity. lncRNAs are newly recognized as regulators of gene expression, transcriptionally and post- transcriptionally.1-3 Unlike messenger RNAs (mRNAs), which localize specifically to the cytoplasm, lncRNAs can occupy various nuclear compartments and/or the cyto- plasm. lncRNAs function via RNA-DNA, RNA-RNA, and RNA-protein interac- tions.2-6 As a result, they affect multiple stages of gene regulation, including place- ment of chromatin marks, mRNA biogenesis, and signaling pathways.
lncRNA expression is tissue- and cell type-specific5,7-9 but less conserved across species than is mRNA expression.10,11 lncRNAs have been linked to the development of several lineages in hematopoiesis and in the immune response. Some lncRNAs were found to be enriched in hematopoietic stem cells (HSCs)12 or dynamically expressed during erythropoiesis.13,14 RNA interference studies have revealed that lncRNAs control HSC self-renewal and differentiation,12 erythroid precursor matu- ration,14 and granulocytic differentiation of hematopoietic stem and progenitor cells (HSPCs).15 Intergenic lncRNA signatures exhibit subset-specificity in T and B lym- phocytes.16-18 lincR-Ccr2-5’AS, together with GATA3, is essential in the regulation
Correspondence:
ZHIJIE WU
zhijie.wu@nih.gov
Received: October 12, 2018. Accepted: November 22, 2018. Pre-published: December 13, 2018.
doi:10.3324/haematol.2018.208926
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/894
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