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The Transcriptome of Human CD34 Hematopoietic Stem-Progenitor Cells

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The Transcriptome of Human CD34 Hematopoietic Stem-Progenitor Cells The transcriptome of human CD34؉ hematopoietic stem-progenitor cells Yeong C. Kima,1, Qingfa Wua,1, Jun Chena,1, Zhenyu Xuanb, Yong-Chul Junga, Michael Q. Zhangb, Janet D. Rowleyc,2, and San Ming Wanga,2 aCenter for Functional Genomics, Division of Medical Genetics, Department of Medicine, Evanston Northwestern Healthcare Research Institute, Northwestern University Feinberg School of Medicine, Evanston, IL 60201; and bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and cDepartment of Medicine, University of Chicago, Chicago, IL 60637 Contributed by Janet D. Rowley, March 31, 2009 (sent for review February 2, 2009) Studying gene expression at different hematopoietic stages provides sequence dataset from human CD34ϩ cells. Our extensive infor- insights for understanding the genetic basis of hematopoiesis. We matics analysis of the sequence data reveals much novel informa- analyzed gene expression in human CD34؉ hematopoietic cells that tion on gene expression in CD34ϩ cells and provides a current view represent the stem-progenitor population (CD34؉ cells). We collected for the gene expression in CD34ϩ cells and a comprehensive and .transcript signatures from CD34؉ cells, including the de uniform resource for studying hematopoiesis and stem cell biology 459,000< novo-generated 3؅ ESTs and the existing sequences of full-length cDNAs, ESTs, and serial analysis of gene expression (SAGE) tags, and Results performed an extensive annotation on this large set of CD34؉ The CD34؉ Transcript Sequences. Since CD34ϩ cells were identified transcript sequences. We determined the genes expressed in CD34؉ as representing the hematopoietic stem-progenitor cells, continuing cells, verified the known genes and identified the new genes of efforts have identified the genes expressed in these cells with different functional categories involved in hematopoiesis, dissected substantial progress. However, because of the limitations of the the alternative gene expression including alternative transcription technologies, the existing data are not adequate to cover the CD34ϩ initiation, splicing, and adenylation, identified the antisense and transcriptome. We used the following 2 approaches to maximally ؉ ϩ noncoding transcripts, determined the CD34 cell-specific gene ex- collect transcript sequences from CD34 cells: GENETICS pression signature, and developed the CD34؉ cell-transcription map i. De novo CD34ϩ 3Ј EST collection: We performed a large-scale in the human genome. Our study provides a current view on gene CD34ϩ 3Ј EST collection from normal human hematopoietic ؉ expression in human CD34 cells and reveals that early hematopoiesis CD34ϩ cells, using a high-throughput generation of long sequences is an orchestrated process with the involvement of over half of the from serial analysis of gene expression (SAGE) tags for gene identifi- human genes distributed in various functions. The data generated cation (GLGI) method (16, 17). By using SAGE tags as the sense from our study provide a comprehensive and uniform resource for primers for PCR, GLGI converts SAGE tags into 3ЈESTs. From 10,000 studying hematopoiesis and stem cell biology. novel SAGE tags obtained in a previous CD34ϩ study (12), we generated 25,798 high-quality 3ЈESTs. This is the largest EST collection gene expression ͉ genome map ͉ annotation ͉ hemotopoiesis ͉ stem cell from human CD34ϩ cells and one of the largest EST collections from a single human cell type using the Sanger sequencing system (http:// ematopoiesis is a dynamic process. Formed in the ventral www.ncbi.nlm.nih.gov/UniGene/lbrowse2.cgi?TAXID ϭ 9606). Hmesoderm at the embryonic stage, hematopoietic stem cells ii. Existing CD34ϩ mRNA sequences collected: We performed migrate progressively to yolk sac, aortic region, placenta, fetal liver, database and literature mining to identify publicly available mRNA and bone marrow in the adult. During the process, the hematopoi- sequences originating from human CD34ϩ cells. These include etic stem cells reproduce themselves by self-renewal and differen- full-length cDNA sequences (8), 5Ј and 3Ј ESTs (7, 8, 16), 21-bp- tiate into the multipotent progenitors, the lineage-restricted pro- longSAGE tags (15), and 14-bp SAGE tags (10, 13). To ensure that genitors, and eventually the mature cell types of erythroid cell, the information generated from the study represents the normal platelet, myeloid cell, monocyte, NK cell, T cell, and B cell in the CD34ϩ transcriptome, we used only the sequences generated from peripheral circulation to perform specified functions (1). CD34, a normal primary CD34ϩ cells. cellular membrane glycoprotein, is a specific marker for the hema- A total of 459,482 CD34ϩ transcript signatures were identified topoietic cells differentiated at the stem-progenitor stage in humans through these processes (Table 1, Dataset S1). They represent the and other mammalian species (2, 3). The CD34ϩ hematopoietic achievement of CD34ϩ transcript identification in the past decade stem-progenitor cells (referred to as CD34ϩ cells hereafter) are using the Sanger sequencing system and provide a solid base for essential for maintaining the entire hematopoietic system and are comprehensive CD34ϩ transcriptome annotation. widely used clinically to restore the hematopoietic system through bone marrow transplantation for treatment of various diseases (4). The Genes Expressed in CD34؉ Cells. We compared the CD34ϩ ϩ The functional importance of CD34 cells has attracted much transcript sequences with 22,828 human genes, including the 18,013 attention to determine the genetic basis of CD34ϩ cells, as exem- plified by analyzing gene expression in CD34ϩ cells with increased scope and identifying multiple genes and pathways associated with Author contributions: M.Q.Z., J.D.R., and S.M.W. designed research; Y.C.K., Q.W., J.C., and CD34ϩ cell-related hematopoietic self-renewal and differentiation Y.-C.J. performed research; Y.C.K., Q.W., Z.X., M.Q.Z., and S.M.W. analyzed data; and J.D.R. and S.M.W. wrote the paper. (5–15). However, the existing knowledge of gene expression in CD34ϩ cells is not comprehensive because the technologies used Conflict of interest: The authors declare no conflict of interest. Data deposition: The 3Ј EST data generated from the study were deposited in NCBI dbEST are limited, the data generated are fractionated in individual studies with accession number GD135551-161348. The genome mapping information is listed at and lack consistent annotation with current genome information, http://projects.bioinformatics.northwestern.edu/wanglab/CD34plus. and the number of genes implicated as key genes associated with 1Y.C.K., Q.W., and J.C. contributed equally to this work. ϩ CD34 cells remains very limited. 2To whom correspondence may be addressed. E-mail: [email protected] or To gain more comprehensive knowledge of the genetic basis of [email protected]. ϩ human CD34 cells, we performed an integrated transcriptome This article contains supporting information online at www.pnas.org/cgi/content/full/ ϩ analysis on human CD34 cells. We generated a large transcript 0903390106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903390106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 26, 2021 Table 1. The sequence sources and genes identified Table 2. Trancription factor, signal, and kinase genes in CD34؉ cells in CD34؉ cells Number Matched Items Total genes Detected* (%) Sequence type (%) (%) Reference Examples of transcription factor gene families Sources of CD34ϩ transcript sequences zf-C2H2 549 327 (60) KRAB 268 162 (60) Full-length cDNA 298 (0.1) 8 Homeobox 204 68 (33) ESTs HLH 104 46 (44) Ј 3 EST 25,798 Current study BTB 53 35 (66) Ј 3 EST 1,591 dbEST SCAN 50 34 (68) Ј 3 EST 214 10 Hormone receptor 48 29 (60) Ј 3 EST 177 6 zf-C4 48 29 (60) Ј 5 EST 13,493 8 bZIP 1 33 26 (79) Ј Oligo-capped 5 EST 1,295 14 ETS 27 18 (67) EST 329 dbEST Fork head 47 18 (38) Subtotal 42,897 (9) PAS 18 15 (83) SAGE tags TIG 14 13 (93) 14-bp SAGE tag 99,954 10 PHD 14 12 (86) 14-bp SAGE tag 117,939 13 GATA 14 11 (79) 21-bp longSAGE tag 198,394 15 MYB DNA-binding 17 11 (65) Subtotal 416,287 (91) Signal pathway genes detected in CD34ϩ cells Total signature 459,482 (100) Calcium signaling pathway 176 44 (25) ϩ ERB B signaling pathway 87 29 (33) Human genes matched by CD34 transcript sequences Hedgehog signaling pathway 57 12 (21) Matched JAK-STAT signaling pathway 155 35 (23) Sequence type genes MAPK signaling pathway 265 66 (25) mTOR signaling pathway 51 14 (27) Full-length sequence 298 293 (98) 265 Notch signaling pathway 46 12 (26) EST 42,897 10,273 (24) 4,989 Phosphatidylinositol signaling system 79 63 (80) SAGE tag 416,287 210,496 (51) 11,629 TGF-␤ signaling pathway 89 27 (30) Total 459,482 221,017 (48) 12,759* VEGF signaling pathway 73 20 (27) WNT signaling pathway 148 50 (34) *The number refers to the nonredundant genes. Kinase genes detected in CD34ϩ cells AGC 69 6 (9) Atypical 39 9 (23) human genes represented by 26,829 RefSeq mRNA sequences and the Calcium/calmodulin regulated kinases 113 10 (9) 14,129 human genes represented by the SAGEmap reference database. Casein kinase 1 17 5 (29) A total of 12,759 (56%) human genes were matched by 221,017 CD34ϩ CMGC 76 9 (12) Receptor guanylate cyclase 8 0 (0) transcript sequences (Table 1, Dataset S2), indicating that over half of STE 53 10 (19) ϩ the human genes are expressed in CD34 cells. Tyrosine kinase-like 49 11 (22) Tyrosine kinases 95 18 (19) (The Functional Categories for the Genes Expressed in CD34؉ Cells. Using Other 101 15 (15 Total 620 (100) 94 (15) the Gene Ontology reference database (18), we performed a global ϩ functional classification for the genes expressed in CD34 cells *The same genes can be classified in different families.
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