Interaction between Hhex and SOX13 Modulates Wnt/TCF Activity

Marfil, Vanessa; Moya, Marta; Pierreux, Christophe E.; Castell, José V.; Lemaigre, Frédéric P.; Real, Francisco X.; Bort, Roque

doi:10.1074/jbc.m109.046649

Cited by 34 publications

(28 citation statements)

References 64 publications

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“…Lef1 expression is primarily controlled by TCF1 (Driskell et al, 2007). Given the precedent that some TCF1 target gene expression can be inhibited by SOX13 (Marfil et al, 2010; Melichar et al, 2007), high amounts of SOX13 in immV2 thymocytes may interfere with TCF1-mediated induction of Lef1 . Consistent with this, immature γδTCR + thymocytes from Sox13 Tg mice expressed significantly lower amounts of LEF1 and CD27 (Figure S3F).…”

Section: Resultsmentioning

confidence: 99%

A Network of High-Mobility Group Box Transcription Factors Programs Innate Interleukin-17 Production

et al. 2013

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SUMMARY How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of High Mobility Group box (HMG) transcription factors, SOX4, SOX13, TCF1 and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46+ ILCs and restrained cytokine production by Lymphoid Tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins.

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Section: Resultsmentioning

confidence: 99%

A Network of High-Mobility Group Box Transcription Factors Programs Innate Interleukin-17 Production

et al. 2013

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“…Based on their early onset of sexually-dimorphic expression, several genes are promising candidates to play an early regulatory role in the male and female pathways (Table S2, Text S1). Sox13 is a member of the SOX protein family that lacks an activation domain but can repress Wnt signaling by forming a complex with the β-catenin cofactor, TCF1 [39], [40]. Mef2c is activated in the XY gonad at E11.6 and has been shown to interact with Sox9 in chondrocytes [41].…”

Section: Discussionmentioning

confidence: 99%

Fine Time Course Expression Analysis Identifies Cascades of Activation and Repression and Maps a Putative Regulator of Mammalian Sex Determination

et al. 2013

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In vertebrates, primary sex determination refers to the decision within a bipotential organ precursor to differentiate as a testis or ovary. Bifurcation of organ fate begins between embryonic day (E) 11.0–E12.0 in mice and likely involves a dynamic transcription network that is poorly understood. To elucidate the first steps of sexual fate specification, we profiled the XX and XY gonad transcriptomes at fine granularity during this period and resolved cascades of gene activation and repression. C57BL/6J (B6) XY gonads showed a consistent ∼5-hour delay in the activation of most male pathway genes and repression of female pathway genes relative to 129S1/SvImJ, which likely explains the sensitivity of the B6 strain to male-to-female sex reversal. Using this fine time course data, we predicted novel regulatory genes underlying expression QTLs (eQTLs) mapped in a previous study. To test predictions, we developed an in vitro gonad primary cell assay and optimized a lentivirus-based shRNA delivery method to silence candidate genes and quantify effects on putative targets. We provide strong evidence that Lmo4 (Lim-domain only 4) is a novel regulator of sex determination upstream of SF1 (Nr5a1), Sox9, Fgf9, and Col9a3. This approach can be readily applied to identify regulatory interactions in other systems.

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“…Hhex encodes a homeobox transcription factor known to be involved in pancreatic and liver development [60,61]. SNPs in HHEX have been associated with decreased insulin secretion perhaps due to alterations in vesicle docking [57,62-66].…”

Section: Discussionmentioning

confidence: 99%

Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets

Yoganathan

Chu

et al. 2013

BMC Genet

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BackgroundGenome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes.ResultsWe identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non-fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose.ConclusionsThese data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes.

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Interaction between Hhex and SOX13 Modulates Wnt/TCF Activity

Cited by 34 publications

References 64 publications

A Network of High-Mobility Group Box Transcription Factors Programs Innate Interleukin-17 Production

A Network of High-Mobility Group Box Transcription Factors Programs Innate Interleukin-17 Production

Fine Time Course Expression Analysis Identifies Cascades of Activation and Repression and Maps a Putative Regulator of Mammalian Sex Determination

Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets

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