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Gene Expression Patterns Define Novel Roles for E47 in Cell Cycle Progression, Cytokine-Mediated Signaling, and T Lineage Development

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Gene Expression Patterns Define Novel Roles for E47 in Cell Cycle Progression, Cytokine-Mediated Signaling, and T Lineage Development Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development Ruth Schwartz*†, Isaac Engel*†‡, Mohammad Fallahi-Sichani§, Howard T. Petrie§, and Cornelis Murre*¶ *Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0377; and §Scripps͞Florida Research Institute, 5353 Parkside Drive, RF-1, Jupiter, FL 33458 Communicated by Michael S. Levine, University of California, Berkeley, CA, May 5, 2006 (received for review April 7, 2006) In maturing T lineage cells, the helix–loop–helix protein E47 has analyze the global patterns of gene expression in E2A-deficient been shown to enforce a critical proliferation and developmental lymphomas in the absence and presence of E47. Cluster analysis checkpoint commonly referred to as ␤ selection. To examine how identified groups of genes that were regulated by E47 and shared E47 regulates cellular expansion and developmental progression, biochemical or physiological properties. These included genes we have used an E2A-deficient lymphoma cell line and DNA involved in cell survival, cell cycle progression, stress response, lipid microarray analysis to identify immediate E47 target genes. Hier- metabolism, ␣␤, and natural killer T (NKT) cell function. Based on archical cluster analysis of gene expression patterns revealed that these observations, we suggest that E47 functions in molecular E47 coordinately regulates the expression of genes involved in cell pathways to coordinate cell survival, cell growth, and developmen- survival, cell cycle progression, lipid metabolism, stress response, tal maturation. We identified cyclin-dependent kinase 6 (Cdk6) as and lymphoid maturation. These include Plc␥2, Cdk6, CD25, Tox, an E47 target gene, providing a potential mechanism underlying a Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2, and Xbp1. role for E47 in cell cycle progression. Socs1 and Socs3 were also We propose a regulatory network linking Janus kinase (JAK)͞signal regulated by E47, and we propose that E47 functions in a cytokine transducer and activator of transcription (STAT)-mediated signal- receptor-mediated regulatory network to regulate Socs gene ex- ing, E47, and suppressor of cytokine signaling (SOCS) proteins in a pression. Interestingly, the regulation of two E47 targets, Hes1 and common pathway. Finally, we suggest that the aberrant activation Gfi1, reflects a conserved regulatory network used in Drosophila of Cdk6 in E47-deficient T lineage cells contributes to the devel- melanogaster sensory organ development. opment of lymphoid malignancy. Results ͉ ͉ ͉ E2A Gfi SOCS Xbp1 Global Gene Expression Patterns in E2A-Deficient Lymphomas in Response to E47 Activity. Our previous observations have indicated ymphocyte development is regulated, in part, by a distinct class a critical role for the E2A proteins in cell survival, growth, and early Lof helix–loop–helix (HLH) proteins, named E proteins (1). Four thymocyte development (1). However, the mechanisms underlying E proteins, E12, E47, E2-2, and HEB, are expressed in developing E47-mediated control of proliferation and differentiation remain to lymphocytes. E12 and E47 are encoded by one gene, designated as be elucidated. As a first approach to this question, we have used E2A, and arise through differential splicing in an exon encoding the oligonucleotide microarrays to identify genes regulated by E47 in HLH domain. E2A-deficient mice exhibit a complete block in B cell E2A-deficient lymphoma cell lines. For this study, we used the 1F9 development at the onset of lineage commitment (2–4). T cell cell line, originally isolated from E2A-deficient thymomas (15). To development is partially blocked in E2A-deficient mice before the identify E47 target genes, 1F9 cells were transduced with a retro- onset of T cell receptor (TCR) ␤ V(D)J gene rearrangement (5–7). virus carrying an E47͞estrogen receptor (E47ER) hybrid protein. E proteins, and E2A proteins in particular, play critical roles in Control cells were transduced with virus carrying the basic HLH regulating developmental progression at the pre-TCR and TCR region but lacking the N-terminal transactivation domain. Both checkpoints (8, 9). Signals emanating from the pre-TCR and TCR retroviral constructs also directed the expression of human CD25 complex act to suppress E protein DNA-binding activity, induce the (hCD25) to allow rapid isolation of transduced cells (16). One day expression of the E protein inhibitor Id3, and lower the abundance after infection, cells were incubated with 4-hydroxytamoxifen (4- of E47 protein levels (10). Lowering the dose of E47 has been OHT) for a period of 6 hours, to activate the E47ER fusion protein. demonstrated to release the block in differentiation and prolifer- hCD25-positive cells were purified by using magnetic beads, and ation observed in thymocytes with defects in pre-TCR expression RNA was isolated and used to generate probes for hybridization to and pre-TCR-mediated signaling (8, 9, 11). The E proteins also murine oligonucleotide microarrays. Approximately 225 genes were function at the TCR checkpoint, because an E2A deficiency has identified whose transcript levels were modulated by the enforced been shown to accentuate positive selection (12). In contrast, expression of E47 (data not shown). The expression pattern asso- positive selection in Id3-ablated mice is blocked, albeit partially ciated with E47 expression appeared to reflect the role of E47 in cell (13). Taken together, these data suggest that the E2A proteins act cycle regulation and T lineage developmental maturation, as dem- as gatekeepers at the pre-TCR and TCR checkpoints, and passage onstrated by the induction of pT␣, Hes1, Xbp1, Eto2, Gadd45a, through these checkpoints requires pre-TCR or TCR-mediated modulation of E2A activity. E proteins also function as tumor suppressors. E2A-deficient Conflict of interest statement: No conflicts declared. mice rapidly develop thymic lymphoma (5, 14). Reintroduction of Abbreviations: DP, double positive; DN, double negative; HLH, helix–loop–helix; Cdk6, E2A activity into cell lines adapted from lymphomas that developed cyclin-dependent kinase 6; TCR, T cell receptor; NKT, natural killer T; T-ALL, T-acute in E2A-ablated mice caused rapid apoptosis (15). In contrast, lymphoblastoid leukemia. enforced expression of E47 in conjunction with Bcl-2 induced cell †R.S. and I.E. contributed equally to this work. cycle arrest, suggesting a direct role for E2A in the suppression of ‡Present address: Division of Developmental Immunology, La Jolla Institute for Allergy and cell growth (11). As a first approach to determine the mechanism Immunology, 10355 Science Center Drive, San Diego, CA 92122. by which E47 inhibits cellular proliferation and promotes develop- ¶To whom correspondence should be addressed. E-mail: [email protected]. mental progression, we have used oligonucleotide microarrays to © 2006 by The National Academy of Sciences of the USA 9976–9981 ͉ PNAS ͉ June 27, 2006 ͉ vol. 103 ͉ no. 26 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0603728103 Downloaded by guest on September 26, 2021 Fig. 1. E47 target genes expressed in an E2A-deficient lymphoma cell line. The 1.F9 cell line was transduced with retrovirus encoding E47 or a truncated form of E47 encoding the basic HLH domain. RNA was isolated from transduced cells and analyzed for target gene expression by using microarray analysis. Selected activated and repressed target genes by the overexpression of E47 are depicted on the top (A) and bottom (B), respectively. Values indicated on the vertical axis IMMUNOLOGY show the fold induction or repression of E47 target transcript levels. Gadd45b, Ets2, Mef2b, Gfi1, Gfi1b, Id2, Socs1, Socs3, and Ror␥,as Cdk6 transcription upon enforced expression of E47 was particu- well as repression of Cdk6, Pou2af1, Icos, Gata3, Ror␣, Foxo1, larly striking. Specifically, Cdk6 transcript levels were reduced by a Lmo4, CD25, and Tox (Fig. 1). To verify the observations obtained factor of 2-fold, 6 hours after tamoxifen treatment (Table 1). This from the microarray analysis, we have used quantitative PCR result was further corroborated by quantitative PCR analysis (Fig. analysis to quantitatively determine transcript levels of CD25, 4). Because Cdk6 activity acts to phosphorylate Rb to regulate cell Socs3, Gadd45a, GAdd45b, and Ror␥ (Fig. 4, which is published as cycle progression, we examined the phosphorylation status of Rb supporting information on the PNAS web site, and results not using Western blotting and Rb-specific antibodies. One day after shown). The data point to a role for E47 in contributing to the induction, Rb phosphorylation significantly declined, consistent transcriptional program that controls lymphoid development by with cell cycle arrest of E2A-deficient lymphomas (R.S. and I.E., acting upstream of transcriptional regulators known to play key unpublished observations). E47 also induced the expression of p21, roles in various proliferation and developmental pathways, includ- Rb, and E2F4, albeit modestly (Table 1). The growth arrest and ing Hes1, Ets2, Gata3, Pou2af1, Foxo1, Xbp1, Ror␥, Gfi1, Gfi1b, DNA damage inducible genes, Gadd45a and Gadd45b, were also and Tox. coordinately induced by E47 expression (Table 1 and data not shown). Taken together, these data indicate that a subset of genes E47 Regulates the Expression of the Cell Cycle Regulator Cdk6. To link involved in cell cycle progression are regulated by E47 in E2A- genes that act together
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