Context-Dependent Regulation of Hematopoietic Lineage Choice by HEBAlt

Wang, Duncheng; Claus, Carol L.; Rajkumar, Paula; Braunstein, Marsela; Moore, Amanda J.; Sigvardsson, Mikael; Anderson, Michele K.

doi:10.4049/jimmunol.0901783

Cited by 12 publications

(15 citation statements)

References 71 publications

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“…However, both isoforms contain DNA binding and dimerization domains, indicating separate functions of the isoforms, and not a simple dominant negative function of the short isoform. Indeed, both the long and short isoform of the TCF12 have previously been described as having distinct functions in thymocyte development [31,32]. Deregulation of Tcf12 has recently been causally implicated in CRC in a DNA transposon based forward genetic screen in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis

et al. 2011

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BackgroundApproximately half of all human genes use alternative transcription start sites (TSSs) to control mRNA levels and broaden the transcriptional output in healthy tissues. Aberrant expression patterns promoting carcinogenesis, however, may arise from alternative promoter usage.ResultsBy profiling 108 colorectal samples using exon arrays, we identified nine genes (TCF12, OSBPL1A, TRAK1, ANK3, CHEK1, UGP2, LMO7, ACSL5, and SCIN) showing tumor-specific alternative TSS usage in both adenoma and cancer samples relative to normal mucosa. Analysis of independent exon array data sets corroborated these findings. Additionally, we confirmed the observed patterns for selected mRNAs using quantitative real-time reverse-transcription PCR. Interestingly, for some of the genes, the tumor-specific TSS usage was not restricted to colorectal cancer. A comprehensive survey of the nine genes in lung, bladder, liver, prostate, gastric, and brain cancer revealed significantly altered mRNA isoform ratios for CHEK1, OSBPL1A, and TCF12 in a subset of these cancer types.To identify the mechanism responsible for the shift in alternative TSS usage, we antagonized the Wnt-signaling pathway in DLD1 and Ls174T colorectal cancer cell lines, which remarkably led to a shift in the preferred TSS for both OSBPL1A and TRAK1. This indicated a regulatory role of the Wnt pathway in selecting TSS, possibly also involving TP53 and SOX9, as their transcription binding sites were enriched in the promoters of the tumor preferred isoforms together with their mRNA levels being increased in tumor samples.Finally, to evaluate the prognostic impact of the altered TSS usage, immunohistochemistry was used to show deregulation of the total protein levels of both TCF12 and OSBPL1A, corresponding to the mRNA levels observed. Furthermore, the level of nuclear TCF12 had a significant correlation to progression free survival in a cohort of 248 stage II colorectal cancer samples.ConclusionsAlternative TSS usage in colorectal adenoma and cancer samples has been shown for nine genes, and OSBPL1A and TRAK1 were found to be regulated in vitro by Wnt signaling. TCF12 protein expression was upregulated in cancer samples and correlated with progression free survival.

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Section: Discussionmentioning

confidence: 99%

Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis

et al. 2011

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“…HEBAlt, a long form of the E protein HEB gene, is specifically expressed in lymphoid precursor cells [34]. In thymic precursors, HEBAlt collaborates with Notch signals to promote early T cell development by suppressing B cell or myeloid potential [35][36]. HEB −/− T cells possess compromised Notch1 function and lose T cell potential [37].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

et al. 2011

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The roles of the reprogramming factors Oct4, Sox2, c-Myc and Klf4 in early T cell development are incompletely defined. Here, we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors (ETPs) differentiate into T cells. Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2-to-DN3 transition when T cell lineage commitment occurs and affected the transcription of a variety of genes with crucial functions in early T cell development, including genes involved in microenvironmental signaling (IL-7Rα), Notch target genes (Deltex1), and essential T cell lineage regulatory or inhibitory genes (Bcl11a, SpiB, and Id1). The survival of thymocytes and the rearrangement at the Tcrb locus were impaired in the presence of enforced Klf4 expression. The defects in the DN1-to-DN2 and DN2-to-DN3 transitions in Klf4 transgenic mice could not be rescued by the introduction of a TCR transgene, but was partially rescued by restoring the expression of IL-7Rα. Thus, our data indicate that the downregulation of Klf4 is a prerequisite for T cell lineage commitment.

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“…We have previously shown that HEBAlt-expressing fetal liver-derived LSK cells are inhibited from becoming B cells and myeloid cells in the presence of high levels of Dll1 (Wang et al, 2010). HEBAlt is upregulated by Notch signaling, suggesting that it could influence DC development.…”

Section: Hebalt Inhibits DC Developmentmentioning

confidence: 99%

“…E2-2 has been shown to play a role in splenic pDC development (Cisse et al, 2008), but the influences of the other E proteins on DC development are unknown. HEBAlt promotes T-cell development downstream of Dll-Notch signaling (Bain et al, 1997;Wang et al, 2010;Wang et al, 2006), and is thus a good candidate for influencing the T/DC fate choice towards the T-cell lineage. Conversely, the E protein antagonist Id2, which is thought to be induced by PU.1 (Anderson et al, 2002), promotes DC development (Hacker et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional priming of intrathymic precursors for dendritic cell development

et al. 2012

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Context-Dependent Regulation of Hematopoietic Lineage Choice by HEBAlt

Abstract: Material

Cited by 12 publications

References 71 publications

Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis

Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

Transcriptional priming of intrathymic precursors for dendritic cell development

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