Runx3 regulates dendritic epidermal T cell development

Department of Veterinary Resources, Weizmann Institute of Science, Israel
Developmental Biology (Impact Factor: 3.55). 04/2007; 303(2):703-14. DOI: 10.1016/j.ydbio.2006.12.005
Source: PubMed


The Runx3 transcription factor regulates development of T cells during thymopoiesis and TrkC sensory neurons during dorsal root ganglia neurogenesis. It also mediates transforming growth factor-beta signaling in dendritic cells and is essential for development of skin Langerhans cells. Here, we report that Runx3 is involved in the development of skin dendritic epidermal T cells (DETCs); an important component of tissue immunoregulation. In developing DETCs, Runx3 regulates expression of the alphaEbeta7 integrin CD103, known to affect migration and epithelial retention of DETCs. It also regulates expression of IL-2 receptor beta (IL-2Rbeta) that mediates cell proliferation in response to IL-2 or IL-15. In the absence of Runx3, the reduction in CD103 and IL-2Rbeta expression on Runx3(-/-) DETC precursors resulted in impaired cell proliferation and maturation, leading to complete lack of skin DETCs in Runx3(-/-) mice. The data demonstrate the requirement of Runx3 for DETCs development and underscore the importance of CD103 and IL-2Rbeta in this process. Of note, while Runx3(-/-) mice lack both DETCs and Langerhans cells, the two most important components of skin immune surveillance, the mice did not develop skin lesions under pathogen-free (SPF) conditions.

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Available from: Ori Brenner, Oct 09, 2014
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    • "RUNX1 (also known as AML1) has been extensively documented as an important factor in hematopoiesis and in the etiology of acute myelogenous leukemia (for review see [11]). RUNX2 has been shown to be involved in bone development (for review see [12]) and RUNX3 was documented as an important TF in development of T-lymphocytes [13]–[15] and has been associated with the pathogenesis of several malignancies [16], including PAC [17], [18]. Hence, the DEMON analysis predicts that RUNX TF family members are top candidates responsible for altered transcription of genes in the PAC consensus data set. "
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    ABSTRACT: Pancreatic adenocarcinoma (PAC) is one of the most intractable malignancies. In order to search for potential new therapeutic targets, we relied on computational methods aimed at identifying transcription factor binding sites (TFBSs) over-represented in the promoter regions of genes differentially expressed in PAC. Though many computational methods have been implemented to accomplish this, none has gained overall acceptance or produced proven novel targets in PAC. To this end we have developed DEMON, a novel method for motif detection. DEMON relies on a hidden Markov model to score the appearance of sequence motifs, taking into account all potential sites in a promoter of potentially varying binding affinities. We demonstrate DEMON's accuracy on simulated and real data sets. Applying DEMON to PAC-related data sets identifies the RUNX family as highly enriched in PAC-related genes. Using a novel experimental paradigm to distinguish between normal and PAC cells, we find that RUNX3 mRNA (but not RUNX1 or RUNX2 mRNAs) exhibits time-dependent increases in normal but not in PAC cells. These increases are accompanied by changes in mRNA levels of putative RUNX gene targets. The integrated application of DEMON and a novel differentiation system led to the identification of a single family member, RUNX3, which together with four of its putative targets showed a robust response to a differentiation stimulus in healthy cells, whereas this regulatory mechanism was absent in PAC cells, emphasizing RUNX3 as a promising target for further studies.
    PLoS ONE 12/2010; 5(12):e14423. DOI:10.1371/journal.pone.0014423 · 3.23 Impact Factor
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    ABSTRACT: Transforming growth factor (TGF beta) prevents T(H)1 and T(H)2 differentiation and converts naive CD4 cells into Foxp3-expressing T regulatory (Treg) cell.(1,2) In sharp contrast, in the presence of pro-inflammatory cytokines, including IL-6, TGF beta not only inhibits Foxp3 expression but also promotes the differentiation of pro-inflammatory IL17-producing CD4 effector T (T(H)17) cells.(3-5) This reciprocal TGF beta-dependent differentiation imposes a critical dilemma between pro- and anti-inflammatory immunity and suggests that a sensitive regulatory mechanism must exist to control TGF beta-driven T(H)17 effector and Treg differentiation. A vitamin A metabolite, retinoic acid (RA), was recently identified as a key modulator of TGF beta-driven-immune deviation capable of suppressing T(H)17 differentiation while promoting Foxp3(+) Treg generation.(6-10)
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