Differential gene expression during terminal erythroid differentiation

Koury, Stephen T.; Yarlagadda, Sushma; Moskalik-Liermo, K.; Popli, N.; Kim, N.; Apolito, C.J.; Peterson, Aidan J.; Zhang, X.; Zu, Peng; Tamburlin, Judith; Bofinger, Diane P.

doi:10.1016/j.ygeno.2007.06.010

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…This conclusion has been supported on a limited basis by gene expression analyses of varying populations of murine and human erythroid cells. 8,[27][28][29][30][31][32][33][34][35] Our transcriptome data strengthen these observations regarding the stage-specific complexity of erythroid differentiation.…”

Section: Discussionsupporting

confidence: 78%

Global transcriptome analyses of human and murine terminal erythroid differentiation

Schulz

et al. 2014

Blood

316

340

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• Transcriptome analyses of human and murine reveal significant stage and speciesspecific differences across stages of terminal erythroid differentiation.• These transcriptomes provide a significant resource for understanding mechanisms of normal and perturbed erythropoiesis.We recently developed fluorescence-activated cell sorting (FACS)-based methods to purify morphologically and functionally discrete populations of cells, each representing specific stages of terminal erythroid differentiation. We used these techniques to obtain pure populations of both human and murine erythroblasts at distinct developmental stages. RNA was prepared from these cells and subjected to RNA sequencing analyses, creating unbiased, stage-specific transcriptomes. Tight clustering of transcriptomes from differing stages, even between biologically different replicates, validated the utility of the FACSbased assays. Bioinformatic analyses revealed that there were marked differences between differentiation stages, with both shared and dissimilar gene expression profiles defining each stage within transcriptional space. There were vast temporal changes in gene expression across the differentiation stages, with each stage exhibiting unique transcriptomes. Clustering and network analyses revealed that varying stage-specific patterns of expression observed across differentiation were enriched for genes of differing function. Numerous differences were present between human and murine transcriptomes, with significant variation in the global patterns of gene expression. These data provide a significant resource for studies of normal and perturbed erythropoiesis, allowing a deeper understanding of mechanisms of erythroid development in various inherited and acquired erythroid disorders. (Blood. 2014;123(22):3466-3477) IntroductionMammalian erythropoiesis is an excellent example of the complex changes in temporal, developmental, and differentiation stage-specific gene expression exhibited by a single cell type.1,2 In the mammalian embryo and fetus, erythroid cells have differing developmental origins, with the primitive erythroid cell lineage developing from yolk sac-derived erythroid progenitors, and the definitive cell lineage maturing from 2 different developmentally regulated stem and progenitor cell populations. [3][4][5][6] These cells have different programs of regulation, with variation in spatial, temporal, and site-specific differentiation.In the adult, mature erythrocytes are the terminally differentiated final cellular product derived from hematopoietic stem and progenitor cells (HSPC). HSPCs undergo a series of lineage choice fate decisions, with increasingly restricted potential, ultimately committing to the erythroid lineage and beginning erythropoiesis. Traditionally, erythropoiesis has been divided into 3 stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation.2 Early erythropoiesis involves commitment of multi-lineage progenitors into erythroid progenitor cells, with proliferation and d...

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Section: Discussionsupporting

confidence: 78%

Global transcriptome analyses of human and murine terminal erythroid differentiation

Schulz

et al. 2014

Blood

316

340

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“…Interestingly, it was recently found to be one of only three differentially expressed genes in the process of terminal erythroid differentiation (Koury et al, 2007), suggesting a potentially complex role in signaling. An intriguing possibility is that STRAD␣/LKB1 export is driven primarily by exportin7 in certain tissues, and by Crm1 in others, and that the exportin7 might direct STRAD␣/LKB1 complex to a specific subset of targets for phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Dorfman

Macara

2008

MBoC

109

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LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD␣ and MO25. STRAD␣ induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD␣/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-␣/␤, STRAD␣ and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD␣ induces nucleocytoplasmic shuttling of LKB1. STRAD␣ facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD␣ inhibits import of LKB1 by competing with importin-␣ for binding to LKB1. MO25 stabilizes the LKB1-STRAD␣ complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRAD␤, isoform which differs from STRAD␣ in the N-and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRAD␤-LKB1 complex might possess unique functions in the nucleus. INTRODUCTIONPeutz-Jeghers cancer syndrome is caused by mutations in a gene encoding a serine/threonine kinase called LKB1 (Hemminki et al., 1998). This kinase is closely related to PAR-4, a protein required for polarization of the Caenorhabditis elegans zygote, and it has recently been implicated in the apical/basal polarization of mammalian epithelial cells (Baas et al., 2004). LKB1 is also involved in numerous cell signaling pathways that regulate cellular metabolism (Shaw et al., 2004Liang et al., 2007), cell growth, and responses to DNA damage (Wei et al., 2005;Setogawa et al., 2006;Zeng and Berger, 2006). LKB1 can phosphorylate and activate 13 protein kinases from the AMP-activated protein kinase family (Lizcano et al., 2004). However, the biological significance of this phosphorylation is still unclear for many of these kinases. The cellular localization and activity of LKB1 is controlled through its interaction with Ste20 Related Adaptor (STRAD) and an adapter protein, MO25 . STRAD, a 48-kDa protein, is a pseudokinase that consists of a STE20-like kinase domain but lacks several residues that are indespensible for catalytic activity. STRAD resembles most closely the STE20 homologues SPAK (Johnston et al., 2000) and ILPIP (Sanna et al., 2002), or PAP kinase (Nishigaki et al., 2003). Whereas SPAK is a true kinase, it was later shown that ILPIP/PAPK is a pseudokinase, similarly to STRAD and that it also interacts with and activates LKB1. Therefore, it was termed STRAD␤, whereas the original STRAD became known as STRAD␣ . The complex of LKB1 and STRAD␣ or -␤ is stabilized by MO25, a 40-kDa protein composed of ␣-helical repeats that are distantly related to the armadillo repeat domain (Milburn et al., 2004). MO25 binds STRAD ...

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“…Terminal erythroid differentiation is the process by which immature precursor cells become erythrocytes in mammals. Exportin‐7 appears to be very important to this event, since its gene expression is time‐dependently up‐regulated by erythropoietin treatment in erythroblasts isolated from the spleens of mice infected with an anaemia‐inducing strain of the Friend leukaemia virus [35]. Its precise role, however, is not clear at present.…”

Section: Importins and Exportins In Cellular Differentiationmentioning

confidence: 99%

Importins and exportins in cellular differentiation

Okada

Ishigami

Suzuki

et al. 2008

J Cellular Molecular Medi

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The importin/exportin transport system provides the machinery involved in nucleocytoplasmic transport. Alterations of the levels of importins and exportins may play crucial roles in development, differentiation and transformation. Employing human leukaemia HL-60 cells, we and others have revealed the differentiation-associated changes in the protein and gene expression of these factors. The recent finding that a switch to the importin-α subtype triggers neural differentiation of embryonic stem cells underscores the importance of nucleocytoplasmic transport factors in cellular events. This review focuses on current research into the roles of importins and exportins in cell differentiation.

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Differential gene expression during terminal erythroid differentiation

Cited by 9 publications

References 51 publications

Global transcriptome analyses of human and murine terminal erythroid differentiation

Global transcriptome analyses of human and murine terminal erythroid differentiation

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Importins and exportins in cellular differentiation

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