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Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [ChIP-Seq]

ABSTRACT: The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insight into the molecular determinants of human congenital asplenia. We performed ChIP-sequencing for Hox11 rep1 and rep2 in eSMC untreated cells.

ORGANISM(S): Mus musculus

SUBMITTER: Andrea Brendolan

PROVIDER: E-GEOD-81660 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [ChIP-Seq]

Project description:The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insight into the molecular determinants of human congenital asplenia.

2016-07-01 | GSE81660 | GEO

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [Microarray Expression]

Project description:The molecular mechanisms underlying asplenia, a condition often associated with overwhelming infections remain largely unknown. During spleen development, the transcription factor TLX1 controls morphogenesis and organ expansion, and loss of it causes spleen agenesis. However, the downstream signaling pathways that are deregulated in the absence of TLX1 are mostly unknown. Herein, we demonstrate that loss of Tlx1 in the splenic mesenchyme causes increased retinoic acid (RA) signaling. Increased RA activity causes premature differentiation of the splenic mesenchyme and reduced vasculogenesis of the splenic anlage. Moreover, excess or deficiency in RA signaling, as observed in Cyp26b1 or Rdh10 mutants respectively, also results in spleen growth arrest. Genome-wide analysis revealed that TLX1 binds RA-associated genes through the AP-1 site and cooperates with the AP-1 family transcription factors to regulate transcription. Pharmacological inhibition of RA signaling partially rescues the spleen defect. These findings establish the critical role of TLX1 in controlling RA metabolism, and provide novel mechanistic insights into the molecular determinants underlying congenital asplenia.

2016-07-01 | GSE68519 | GEO

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [Microarray Expression]

2016-07-01 | E-GEOD-68519 | biostudies-arrayexpress

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development

Project description:Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development

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TLX1 ChIP-Seq in ALL-SIL

Project description:The T-cell leukemia homeobox 1 (TLX1, HOX11) transcription factor is critically involved in the multistep pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanisms by which these T-cell specific oncogenes cooperate during transformation remain to be established. Here, we used an integrative genomics approach to show that the oncogenic properties of TLX1 are mediated by genome-wide interference with the ETS1 and RUNX1 transcription factors. Partial disruption of ETS1 and RUNX1 activity by ectopic TLX1 expression in immature thymocytes drives repression of T-cell specific super-enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 signaling. These phenomena coordinately trigger a TLX1 driven pre-leukemic phenotype in human thymic precursor cells, which corresponds with the in vivo thymic regression observed in murine TLX1 tumor models, and creates a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multistep pathogenesis of TLX1 driven human leukemia.

2015-08-05 | GSE62264 | GEO

Ectopic Expression data of TLX1 in Hematopoietic Progenitors in TLX1 Transgenic Mice Deficient in DNA-PK

Project description:The noncluster homeodomain containing gene, HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell Acute Lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHµ-TLX1Tg mice, which developed mature B cell lymphoma after a long latency period suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHµ-TLX1Tg mice with PrkdcScid/Scid mice; To identify the molecular pathways dysregulated in the earliest stages of TLX1-induced transformation, we used Affimetrix microarrays to compare gene expression profiling of premaliganant thymocytes (6~8 weeks old): DN1, DN2 and DN3 stages from HOX11 transgenic PrkdcScid/Scid (HOXSCID) mice with the same stage thymocytes from the sex and age matched control PrkdcScid/Scid (SCID) mice. Expression analysis of IgH-TLX1TgPrkdcScid/Scid thymocytes revealed dysregulated expression of cell cycle, apoptotic, mitotic spindle and anaphase-promoting complex genes in double negative (DN) 2 and DN3 stage thymocytes. Moreover, DN1, DN2 and DN3 TLX1-expressing thymocytes showed downregulated expression of ribosomal and mitochondria ribosomal protein genes.

2014-04-05 | GSE47421 | GEO

TLX1 ChIP-Seq in ALL-SIL

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PolyA+ RNA-seq in ALL-SIL upon TLX1 knockdown

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer resulting from malignant transformation of T-cell precursors. Several oncogenes, including the ‘T-cell leukemia homeobox 1’ TLX1 (HOX11) transcription factor, have been identified as early driver events that cooperate with other genetic aberrations in leukemic transformation of progenitor T-cells. The TLX1 controlled transcriptome in T-ALL has been investigated extensively in the past in terms of protein-coding genes, but remains unexplored thus far at the level of long non-coding RNAs (lncRNAs), the latter renown as well-established versatile and key players implicated in various cancer hallmarks. In this study, we present the first extensive analysis of the TLX1 regulated transcriptome focusing on lncRNA expression patterns. We present an integrative analysis of polyA and total RNA sequencing of ALL-SIL lymphoblasts with perturbed TLX1 expression and a primary T-ALL patient cohort (including 5 TLX1+ and 12 TLX3+ cases). We expanded our initially presented dataset of TLX1 and H3K27ac ChIP data in ALL-SIL cells (Durinck et al., Leukemia, 2015) with H3K4me1, H3K4me3, and ATAC-seq data to accurately define (super-) enhancer marked lncRNAs and assigned potential functional annotations to candidate TLX1-controlled lncRNAs through an in silico guilt-by-association approach. Our study paves the way for further functional analysis of selected lncRNAs as potential novel therapeutic targets for a precision medicine approach in the context of T-ALL.

2018-09-11 | GSE110632 | GEO

Total RNA-seq in ALL-SIL upon TLX1 knockdown

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Ectopic Expression data of TLX1 in Hematopoietic Progenitors in TLX1 Transgenic Mice Deficient in DNA-PK

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