Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB

Brabletz, Thomas; Jung, Andreas; Hlubek, Falk; Löhberg, Christian; Meiler, Jens; Suchy, Ulrike; Kirchner, Thomas

doi:10.1093/intimm/11.10.1701

Cited by 54 publications

(43 citation statements)

References 35 publications

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“…Instead, in cMyb seems broadly expressed in the early ectoderm of HH3-4 embryos (Fig. 4I), confirming reported northern and western blots (Karafiat et al, 2005), and providing further support for the possible participation of cMyb in Pax7 regulation.cMyb and ETS1 are known to cooperate in many different contexts (Dudek et al, 1992;McCracken et al, 1994;Postigo et al, 1997;Ratajczak et al, 1998;Brabletz et al, 1999;Betancur et al, 2010a). As there are ETS1 sites present in P7eNPBEΔ2, we tested the possible cooperation between ETS1 and cMyb to regulate P7eNPBE.…”

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confidence: 80%

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Pax7 is regulated by cMyb during early neural crest development through a novel enhancer

et al. 2013

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SUMMARYThe neural crest (NC) is a migratory population of cells unique to vertebrates that generates many diverse derivatives. NC cells arise during gastrulation at the neural plate border (NPB), which is later elevated as the neural folds (NFs) form and fuse in the dorsal region of the closed neural tube, from where NC cells emigrate. In chick embryos, Pax7 is an early marker, and necessary component of NC development. Unlike other early NPB markers, which are co-expressed in lateral ectoderm, medial neural plate or posterior-lateral mesoderm, Pax7 early expression seems more restricted to the NPB. However, the molecular mechanisms controlling early Pax7 expression remain poorly understood. Here, we identify a novel enhancer of Pax7 in avian embryos that replicates the expression of Pax7 associated with early NC development. Expression from this enhancer is found in early NPB, NFs and early emigrating NC, but unlike Pax7, which is also expressed in mesodermal derivatives, this enhancer is not active in somites. Further analysis demonstrates that cMyb is able to interact with this enhancer and modulates reporter and endogenous early Pax7 expression; thus, cMyb is identified as a novel regulator of Pax7 in early NC development. KEY WORDS: Neural plate border, Neural crest, PAX7, cMyb, Enhancer, ChickPax7 is regulated by cMyb during early neural crest development through a novel enhancerStephanie Vadasz, Jonathan Marquez, Maria Tulloch, Natalia A. Shylo and Martín I. García-Castro* DEVELOPMENT 3692 regulatory elements and TFs that initiate the expression of Pax7 at the NPB have not been reported.Here, we identify a novel Pax7 cis-regulatory element that directs expression in the avian NPB, NFs and early migrating NC cells, similar to the endogenous Pax7 expression associated with early NC. This element does not provide expression in later NC or in mesoderm, where endogenous Pax7 is seen. Through mutagenesis and overexpression studies, we unveil cMyb as a regulator of this enhancer and of endogenous early Pax7 expression. Our study is the first to demonstrate the ability of cMyb to regulate a border specifier directly during NC development and thus proposes a fundamental role for cMyb during the early phases of the NC-GRN. MATERIALS AND METHODS Sequence conservation and TF-binding analysisSequence conservation was determined using VISTA Browser (Visel et al., 2007), over a 50 bp window with 70% conserved identity. Putative TFbinding sites were identified using the JASPAR core vertebrate database (Bryne et al., 2008). Plasmid constructsEnhancer constructs were PCR amplified (DNeasy Kit, Qiagen) from genomic chick or human DNA (a gift from J. Noonan, New Haven, CT, USA), and cloned into ptkEGFP (a gift from H. Kondoh, Osaka, Japan) or ptkmCherry (a gift from D. Meulemans, Boulder, CO, USA) using KpnI and XhoI. pRFP was generated by removing the miRNA cassette from pRFPRNAi (ARK Genomics). Deletion constructs were generated by first amplifying each end with primers containing 15 bp of internal overlapping sequence fol...

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supporting

confidence: 80%

“…cMyb and ETS1 are known to cooperate in many different contexts (Dudek et al, 1992;McCracken et al, 1994;Postigo et al, 1997;Ratajczak et al, 1998;Brabletz et al, 1999;Betancur et al, 2010a). As there are ETS1 sites present in P7eNPBEΔ2, we tested the possible cooperation between ETS1 and cMyb to regulate P7eNPBE.…”

Section: Research Articlementioning

confidence: 99%

Pax7 is regulated by cMyb during early neural crest development through a novel enhancer

et al. 2013

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“…However, these studies were done using a T cell clone (DH10) that has already committed to the CD4 ϩ Th lineage. ZEB is another transcription factor found to repress CD4 expression, but again only in SP thymocytes, postpositive selection (8). The 434-bp CD4 silencer (3, 4) contains a remarkable five consensus binding sites for runt family transcription factors, making any runt family transcription factors that are expressed in DP thymocytes strong candidates for the factor responsible for down-regulation of CD4 in maturing thymocytes.…”

Section: Cd8mentioning

confidence: 99%

Localization of the Domains in Runx Transcription Factors Required for the Repression of CD4 in Thymocytes

Telfer

Hedblom

Anderson

et al. 2004

The Journal of Immunology

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The runt family transcription factors Runx1 and Runx3 are expressed in developing murine thymocytes. We show that enforced expression of full-length Runx1 in CD4−CD8− thymocytes results in a profound suppression of immature CD4/CD8 double-positive thymocytes and mature CD4 single-positive thymocytes compared with controls. This effect arises from Runx1- or Runx3-mediated repression of CD4 expression, and is independent of positively selecting signals. Runx1 is able to repress CD4 in CD4/CD8 double-positive thymocytes, but not in mature splenic T cells. Runx-mediated CD4 repression is independent of association with the corepressors Groucho/TLE or Sin3. Two domains are required for complete Runx-mediated CD4 repression. These are contained within Runx1 aa 212–262 and 263–360. The latter region contains the nuclear matrix targeting sequence, which is highly conserved among runt family transcription factors across species. The presence of the nuclear matrix targeting sequence is required for Runx-mediated CD4 repression, suggesting that Runx transcription factors are stabilized on the CD4 silencer via association with the nuclear matrix.

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“…11 For the T-lineage, ZEB1 regulates T-cell development. [12][13][14] Loss of ZEB1 in knockout mice accelerates the development of adult T-cell leukemia. 15 In this study, we found that H. pylori-positive gastric diffuse large B-cell lymphomas had less lymph node metastasis and a better response to chemotherapy.…”

mentioning

confidence: 99%

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

et al. 2014

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Primary gastric diffuse large B-cell lymphomas may or may not have a concurrent component of mucosaassociated lymphoid tissue lymphoma. Diffuse large B-cell lymphoma/mucosa-associated lymphoid tissue lymphomas are often associated with Helicobacter pylori (H. pylori) infection, suggesting that the large cells are transformed from mucosa-associated lymphoid tissue lymphomas. In contrast, only limited data are available on the clinical and molecular features of pure gastric diffuse large B-cell lymphomas. In 102 pure gastric diffuse large B-cell lymphomas, we found H. pylori infection in 53% of the cases. H. pylori-positive gastric diffuse large B-cell lymphomas were more likely to present at an earlier stage (73% vs 52% at stage I/II, P ¼ 0.03), to achieve complete remission (75% vs 43%, P ¼ 0.001), and had a better 5-year disease-free survival rate (73% vs 29%, Po0.001) than H. pylori-negative gastric diffuse large B-cell lymphomas. Through genome-wide expression profiles of both miRNAs and mRNAs in nine H. pylori-positive and nine H. pylori-negative gastric diffuse large B-cell lymphomas, we identified inhibition of ZEB1 (zinc-finger E-box-binding homeobox 1) by miR-200 in H. pylori-positive gastric diffuse large B-cell lymphomas. ZEB1, a transcription factor for marginal zone B cells, can suppress BCL6, the master transcription factor for germinal center B cells. In 30 H. pylori-positive and 30 H. pylori-negative gastric diffuse large B-cell lymphomas, we confirmed that H. pylori-positive gastric diffuse large B-cell lymphomas had higher levels of miR-200 by qRT-PCR, and lower levels of ZEB1 and higher levels of BCL6 using immunohistochemistry. As BCL6 is a known predictor of a better prognosis in gastric diffuse large B-cell lymphomas, our data demonstrate that inhibition of ZEB1 by miR-200, with secondary increase in BCL6, is a molecular event that characterizes H. pylori-positive gastric diffuse large B-cell lymphomas with a less aggressive behavior.

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Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB

Cited by 54 publications

References 35 publications

Pax7 is regulated by cMyb during early neural crest development through a novel enhancer

Pax7 is regulated by cMyb during early neural crest development through a novel enhancer

Localization of the Domains in Runx Transcription Factors Required for the Repression of CD4 in Thymocytes

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

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