During mammalian embryogenesis, hematopoietic stem and progenitor cells (HSPCs) originate from mesoderm-derived endothelial cells in the aorta-gonad-mesonephros (AGM) region and placenta (PL). Later, HSPCs expand in fetal liver (FL) and migrate to bone marrow (BM) shortly before birth. Understanding global transcriptional regulation governing HSPC emergence from embryonic stem/induced pluripotent stem cells is necessary to devise clinical applications, such as novel transplantation approaches. In this study, to assess transcriptional dynamics during development, we performed cap analysis of gene expression on 10 developmental murine HSPC populations isolated from the AGM region, PL, FL, and BM and identified 15,681 transcripts across HSPC ontogeny. We performed microarray analysis of AGM-derived HSPCs at 9.5 and 10.5 days postcoitum (dpc) and identified 40 differentially expressed genes, 23 confirmed as significantly changed by real-time polymerase chain reaction. We conclude that a transcriptional switch point occurs in HSPC ontogeny between 9.5 and 10.5 dpc in the AGM region.
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References
1.
SeitaJ and WeissmanIL. (2010). Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med, 2:640–653.
2.
MikkolaHK and OrkinSH. (2006). The journey of developing hematopoietic stem cells. Development, 133:3733–3744.
3.
SugiyamaD, Inoue-YokooT, FraserST, KulkeawK, MizuochiC and HorioY. (2011). Embryonic regulation of the mouse hematopoietic niche. ScientificWorldJournal, 11:1770–1780.
4.
SasakiT, MizuochiC, HorioY, NakaoK, AkashiK and SugiyamaD. (2010). Regulation of hematopoietic cell clusters in the placental niche through SCF/Kit signaling in embryonic mouse. Development, 137:3941–3952.
5.
SwainA, InoueT, TanKS, NakanishiY and SugiyamaD. (2014). Intrinsic and extrinsic regulation of mammalian hematopoiesis in the fetal liver. Histol Histopathol, 29:1077–1082.
6.
KimYC, WuQ, ChenJ, XuanZ, JungYC, ZhangMQ, RowleyJD and WangSM. (2009). The transcriptome of human CD34+ hematopoietic stem-progenitor cells. Proc Natl Acad Sci U S A, 106:8278–8283.
7.
WilhelmBT, BriauM, AustinP, FaubertA, BoucherG, ChagnonP, HopeK, GirardS, MayotteN, et al. (2011). RNA-seq analysis of 2 closely related leukemia clones that differ in their self-renewal capacity. Blood, 117:e27–e38.
8.
LenhardB, SandelinA and CarninciP. (2012). Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat Rev Genet, 13:233–245.
9.
AnderssonR, GebhardC, Miguel-EscaladaI, HoofI, BornholdtJ, BoydM, ChenY, ZhaoX, SchmidlC, et al. (2014). An atlas of active enhancers across human cell types and tissues. Nature, 507:455–461.
10.
CarninciP, KasukawaT, KatayamaS, GoughJ, FrithMC, MaedaN, OyamaR, RavasiT, LenhardB, et al. (2005). The transcriptional landscape of the mammalian genome. Science, 309:1559–1563.
11.
ForrestAR, KawajiH, RehliM, BaillieJK, de HoonMJ and HaberleV and LassmanT and KulakovskiyIV and LizioM, et al. (2014). A promoter-level mammalian expression atlas. Nature, 507:462–470.
12.
Kanamori-KatayamaM, ItohM, KawajiH, LassmannT, KatayamaS, KojimaM, BertinN, KaihoA, NinomiyaN, et al. (2011). Unamplified cap analysis of gene expression on a single-molecule sequencer. Genome Res, 21:1150–1159.
13.
MizuochiC, FraserST, BiaschK, HorioY, KikushigeY, TaniK, AkashiK, TavianM and SugiyamaD. (2012). Intra-aortic clusters undergo endothelial to hematopoietic phenotypic transition during early embryogenesis. PLoS One, 7:e35763.
14.
KaufmanMH. The Atlas of Mouse Development. (1992). Elsevier Academic Press, London.
15.
OttersbachK and DzierzakE. (2005). The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell, 8:377–387.
16.
EmaH and NakauchiH. (2000). Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood, 95:2284–2288.
17.
JoshiA, HannahR, DiamantiE and GottgensB. (2013). Gene set control analysis predicts hematopoietic control mechanisms from genome-wide transcription factor binding data. Exp Hematol, 41:354–366.e14.
18.
YeT, KrebsAR, ChoukrallahMA, KeimeC, PlewniakF, DavidsonI and ToraL. (2011). seqMINER: an integrated ChIP-seq data interpretation platform. Nucleic Acids Res, 39:e35.
19.
Huang daW, ShermanBT and LempickiRA. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 4:44–57.
20.
WilsonNK, FosterSD, WangX, KnezevicK, SchutteJ, KaimakisP, ChilarskaPM, KinstonS, OuwehandWH, et al. (2010). Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell, 7:532–544.
21.
FanR, BondeS, GaoP, SotomayorB, ChenC, MouwT, ZavazavaN and TanK. (2012). Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells. Blood, 119:e139–e147.
22.
TanakaY, JoshiA, WilsonNK, KinstonS, NishikawaS and GottgensB. (2012). The transcriptional programme controlled by Runx1 during early embryonic blood development. Dev Biol, 366:404–419.
23.
HeinzS, BennerC, SpannN, BertolinoE, LinYC, LasloP, ChengJX, MurreC, SinghH and GlassCK. (2010). Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell, 38:576–589.
24.
HogartA, LichtenbergJ, AjaySS, AndersonS, MarguliesEH and BodineDM. (2012). Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites. Genome Res, 22:1407–1418.
25.
DuP, KibbeWA and LinSM. (2008). lumi: a pipeline for processing Illumina microarray. Bioinformatics, 24:1547–1548.
26.
BolstadBM, IrizarryRA, AstrandM and SpeedTP. (2003). A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics, 19:185–193.
27.
GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, DudoitS, EllisB, GautierL, GeY, et al. (2004). Bioconductor: open software development for computational biology and bioinformatics. Genome Biol, 5:R80.
28.
GentlemanR, CareyVJ, DudoitS, IrizarryR, and HuberW(2005). Limma: linear models for microarray data. In: Bioinformatics and Computational Biology Solutions Using R and Bioconductor. SmythGK, ed. Springer, New York.
29.
SaeedAI, SharovV, WhiteJ, LiJ, LiangW, BhagabatiN, BraistedJ, KlapaM, CurrierT, et al. (2003). TM4: a free, open-source system for microarray data management and analysis. Biotechniques, 34:374–378.
30.
NishikawaSI, NishikawaS, HirashimaM, MatsuyoshiN and KodamaH. (1998). Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development, 125:1747–1757.
31.
YokomizoT and DzierzakE. (2010). Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos. Development, 137:3651–3661.
32.
CumanoA, FerrazJC, KlaineM, Di SantoJP and GodinI. (2001). Intraembryonic, but not yolk sac hematopoietic precursors, isolated before circulation, provide long-term multilineage reconstitution. Immunity, 15:477–485.
33.
YoshidaH, TakakuraN, HirashimaM, KataokaH, TsuchidaK, NishikawaS and NishikawaS. (1998). Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family. Dev Comp Immunol, 22:321–332.
34.
KumanoK, ChibaS, KunisatoA, SataM, SaitoT, Nakagami-YamaguchiE, YamaguchiT, MasudaS, ShimizuK, et al. (2003). Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity, 18:699–711.
35.
YoderMC, HiattK, DuttP, MukherjeeP, BodineDM and OrlicD. (1997). Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity, 7:335–344.
36.
MedvinskyA and DzierzakE. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell, 86:897–906.
37.
RybtsovS, SobiesiakM, TaoudiS, SouilholC, SenserrichJ, LiakhovitskaiaA, IvanovsA, FramptonJ, ZhaoS and MedvinskyA. (2011). Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. J Exp Med, 208:1305–1315.
38.
TaoudiS, GonneauC, MooreK, SheridanJM, BlackburnCC, TaylorE and MedvinskyA. (2008). Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell, 3:99–108.
39.
Garcia-PorreroJA, ManaiaA, JimenoJ, LaskyLL, Dieterlen-LievreF and GodinIE. (1998). Antigenic profiles of endothelial and hemopoietic lineages in murine intraembryonic hemogenic sites. Dev Comp Immunol, 22:303–319.
40.
FraserST, OgawaM, YokomizoT, ItoY, NishikawaS and NishikawaS. (2003). Putative intermediate precursor between hematogenic endothelial cells and blood cells in the developing embryo. Dev Growth Differ, 45:63–75.
41.
EichlerGS, HuangS and IngberDE. (2003). Gene Expression Dynamics Inspector (GEDI): for integrative analysis of expression profiles. Bioinformatics, 19:2321–2322.
42.
DavuluriRV, SuzukiY, SuganoS, PlassC and HuangTH. (2008). The functional consequences of alternative promoter use in mammalian genomes. Trends Genet, 24:167–177.
43.
StamatoyannopoulosJA, SnyderM, HardisonR, RenB, GingerasT, GilbertDM, GroudineM, BenderM, KaulR, et al. (2012). An encyclopedia of mouse DNA elements (Mouse ENCODE). Genome Biol, 13:418.
44.
PhillipsJE and CorcesVG. (2009). CTCF: master weaver of the genome. Cell, 137:1194–1211.
45.
HornPA, TeschH, StaibP, KubeD, DiehlV and VoliotisD. (1999). Expression of AC133, a novel hematopoietic precursor antigen, on acute myeloid leukemia cells. Blood, 93:1435–1437.
46.
HirschE, IglesiasA, PotocnikAJ, HartmannU and FasslerR. (1996). Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins. Nature, 380:171–175.
47.
SugiyamaD, KulkeawK and MizuochiC. (2013). TGF-beta-1 up-regulates extra-cellular matrix production in mouse hepatoblasts. Mech Dev, 130:195–206.
48.
LevyDE, KesslerDS, PineR, Reich andN, DarnellJEJr., (1988). Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev, 2:383–393.
49.
EssersMA, OffnerS, Blanco-BoseWE, WaiblerZ, KalinkeU, DuchosalMA and TrumppA. (2009). IFNalpha activates dormant haematopoietic stem cells in vivo. Nature, 458:904–908.
50.
JoshiA, Van de PeerY and MichoelT. (2008). Analysis of a Gibbs sampler method for model-based clustering of gene expression data. Bioinformatics, 24:176–183.
51.
ZhaoX, ValenE, ParkerBJ and SandelinA. (2011). Systematic clustering of transcription start site landscapes. PLoS One, 6:e23409.
52.
McKinney-FreemanS, CahanP, LiH, LacadieSA, HuangHT, CurranM, LoewerS, NaveirasO, KathreinKL, et al. (2012). The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell, 11:701–714.
53.
BerntKM, ZhuN, SinhaAU, VempatiS, FaberJ, KrivtsovAV, FengZ, PuntN, DaigleA, et al. (2011). MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell, 20:66–78.
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