Iroquois Homeodomain transcription factors in ventricular conduction system and arrhythmia

Hu, Wen‐Yu; Xin, Yanguo; Zhang, Lin; Hu, Jian; Sun, Yingxian; Zhao, Yinan

doi:10.7150/ijms.25140

Cited by 15 publications

(14 citation statements)

References 115 publications

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“…Among the strongest downregulated genes ( Figure 2D) are several major urinary proteins (Mups), also known as α 2 µ-globulins, such as Mup19, Mup21, Mup15, Mup17, Mup-ps16, Mup-ps14 and Mup12. Expression of Mup proteins is known to be induced by androgens and they are physiologically relevant, because they bind small hydrophobic molecules, such as steroid hormones, lipids and retinoids in plasma [40]; several cytochrome P450 enzymes; the sushi domain-containing protein 4 (SUSD4) which inhibits complement factors [41]; calpains (e.g., capn11, Capn8) that act as calcium-dependent cysteine proteases, fatty acid elongase 3 (Elovl3); and roquois homeobox protein 1 (lrx1-6) that is known as a cardiac transcription factor [42]. The role of many of these differential genes in liver fibrosis remains unknown.…”

Section: Rna-seq Demonstrates Downregulation Of Pericentral and Upregmentioning

confidence: 99%

Influence of Liver Fibrosis on Lobular Zonation

Ghallab

Myllys

Holland

et al. 2019

Cells

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Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

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Section: Rna-seq Demonstrates Downregulation Of Pericentral and Upregmentioning

confidence: 99%

Influence of Liver Fibrosis on Lobular Zonation

Ghallab

Myllys

Holland

et al. 2019

Cells

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“…In drosophila, the Iroquois gene (IRO) encodes a prepattern gene that controls the formation of bristles on the thorax [7]. In human, the Iroquois homeobox (IRX) family consists of six members (IRX1-IRX6) that contain a homeobox and a so called IRO box [8]. The IRX gene are transcription factors that play key roles in differentiation and development [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…The IRX gene are transcription factors that play key roles in differentiation and development [9,10]. These six IRX genes are organized into two clusters of three, each are located on cytoband 5p15.33 (IRX1, IRX2, and IRX4) and on cytoband 16q12.2 (IRX3, IRX5, and IRX6) [5,8].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Inactivation of the Tumor Suppressor IRX1 Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis

Küster

Schneider

Richter

et al. 2020

Cancers

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Iroquois homeobox (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the IRX1 gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the IRX1 promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant IRX1 methylation was significantly correlated with reduced IRX1 expression. In normal lung samples, the IRX1 promoter showed lower median DNA methylation levels (<10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of IRX1 was detected in ADC and SQCC compared to matching normal lung samples (p < 0.0001). Low IRX1 expression was significantly correlated with impaired prognosis of ADC patients (p = 0.001). Reduced survival probability was also associated with higher IRX1 promoter methylation (p = 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated IRX1 expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of IRX1. On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that IRX1 is negatively correlated with oncogenic pathways and IRX1 expression induces the proapoptotic regulator BAX. In conclusion, we report that IRX1 expression is significantly associated with improved survival probability of ADC patients. IRX1 hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that IRX1 acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer.

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“…IRX2 was shown to participate in cerebellum formation and potentially the ventricular conduction system (VCS) [ 89 , 90 ], while IRX3 was shown to have a definitive role in establishing fast conduction in the VCS [ 90 ]. The downregulation of IRX2 and 3 in endothelial cell lineage suggested that these factors may have an inhibitory role in processes related to endothelial-specific function.…”

Section: Resultsmentioning

confidence: 99%

In Silico Analysis to Explore Lineage-Independent and -Dependent Transcriptional Programs Associated with the Process of Endothelial and Neural Differentiation of Human Induced Pluripotent Stem Cells

Nakhaei‐Nejad

Trinity

Jabbari

et al. 2021

JCM

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Despite a major interest in understanding how the endothelial cell phenotype is established, the underlying molecular basis of this process is not yet fully understood. We have previously reported the generation of induced pluripotent stem cells (iPS) from human umbilical vein endothelial cells and differentiation of the resulting HiPS back to endothelial cells (Ec-Diff), as well as neural (Nn-Diff) cell lineage that contained both neurons and astrocytes. Furthermore, the identities of these cell lineages were established by gene array analysis. Here, we explored the same arrays to gain insight into the gene alteration processes that accompany the establishment of endothelial vs. non-endothelial neural cell phenotypes. We compared the expression of genes that code for transcription factors and epigenetic regulators when HiPS is differentiated into these endothelial and non-endothelial lineages. Our in silico analyses have identified cohorts of genes that are similarly up- or downregulated in both lineages, as well as those that exhibit lineage-specific alterations. Based on these results, we propose that genes that are similarly altered in both lineages participate in priming the stem cell for differentiation in a lineage-independent manner, whereas those that are differentially altered in endothelial compared to neural cells participate in a lineage-specific differentiation process. Specific GATA family members and their cofactors and epigenetic regulators (DNMT3B, PRDM14, HELLS) with a major role in regulating DNA methylation were among participants in priming HiPS for lineage-independent differentiation. In addition, we identified distinct cohorts of transcription factors and epigenetic regulators whose alterations correlated specifically with the establishment of endothelial vs. non-endothelial neural lineages.

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Iroquois Homeodomain transcription factors in ventricular conduction system and arrhythmia

Cited by 15 publications

References 115 publications

Influence of Liver Fibrosis on Lobular Zonation

Influence of Liver Fibrosis on Lobular Zonation

Epigenetic Inactivation of the Tumor Suppressor IRX1 Occurs Frequently in Lung Adenocarcinoma and Its Silencing Is Associated with Impaired Prognosis

In Silico Analysis to Explore Lineage-Independent and -Dependent Transcriptional Programs Associated with the Process of Endothelial and Neural Differentiation of Human Induced Pluripotent Stem Cells

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