PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation

Kolodziej, Stephan; Kuvardina, Olga N.; Oellerich, Thomas; Herglotz, Julia; Backert, Ingo; Kohrs, Nicole; Buscató, Estel la; Wittmann, Sandra K.; Salinas-Riester, Gabriela; Bönig, Halvard; Karas, Michael; Serve, Hubert; Proschak, Ewgenij; Lausen, Jörn

doi:10.1038/ncomms4995

Cited by 59 publications

(65 citation statements)

References 69 publications

(101 reference statements)

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“…28,29 Sequences of primer pairs used for ChIP-polymerase chain reaction (PCR) are available upon request. DNA recovery was calculated as percentage of the input.…”

Section: Chip Assaysmentioning

confidence: 99%

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RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation

Kuvardina

Herglotz

Kolodziej

et al. 2015

Blood

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Key Points• RUNX1 inhibits erythroid differentiation by downregulation of the erythroid gene expression program.• RUNX1 can act as an activator and repressor during megakaryocytic differentiation and counteracts the activity of TAL1.The activity of antagonizing transcription factors represents a mechanistic paradigm of bidirectional lineage-fate control during hematopoiesis. At the megakaryocytic/erythroid bifurcation, the crossantagonism of krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) has such a decisive role. However, how this antagonism is resolved during lineage specification is poorly understood. We found that runt-related transcription factor 1 (RUNX1) inhibits erythroid differentiation of murine megakaryocytic/erythroid progenitors and primary human CD34 1 progenitor cells. We show that RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation by epigenetic repression of the erythroid master regulator KLF1. RUNX1 binding to the KLF1 locus is increased during megakaryocytic differentiation and counterbalances the activating role of T-cell acute lymphocytic leukemia 1 (TAL1). We found that corepressor recruitment by RUNX1 contributes to a block of the KLF1-dependent erythroid gene expression program.Our data indicate that the repressive function of RUNX1 influences the balance between erythroid and megakaryocytic differentiation by shifting the balance between KLF1 and FLI1 in the direction of FLI1. Taken together, we show that RUNX1 is a key player within a network of transcription factors that represses the erythroid gene expression program. (Blood. 2015;125(23):3570-3579) IntroductionThe hematopoietic system is in a constant process of cell proliferation, differentiation, and cell death. Progenitor cells produced by hematopoietic stem cells undergo a hierarchical progression in which the selfrenewal capability is lost and a specific lineage determination is adopted. [1][2][3] In this process, genes important for stem cell functions are downregulated and the expression of genes important for differentiation and cell type-specific functions is upregulated. Transcription factors initiate and maintain cell-specific expression by binding to regulatory sequences of target genes and by recruitment of generegulative complexes with DNA-and histone-modifying activity. These epigenetic modifications reorganize the chromatin locally and genome-wide to sustain a cell type-specific gene expression pattern. [4][5][6] Antagonizing transcription factors play an important role in the establishment of cell type-specific gene expression programs during hematopoietic differentiation. 7 At the megakaryocytic/erythroid bifurcation, the crossantagonism of the transcription factors krueppel-like factor 1 (KLF1) and friend leukemia integration 1 (FLI1) plays such a decisive role. 8,9 However, the mechanism of how this antagonism is resolved is poorly understood. During differentiation of common megakaryocyte/erythroid progenitor cells (MEPs) 10 toward the megakaryoc...

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“…28,29 Sequences of primer pairs used for ChIP-polymerase chain reaction (PCR) are available upon request. DNA recovery was calculated as percentage of the input.…”

Section: Chip Assaysmentioning

confidence: 99%

“…30 Coimmunoprecipitation from K562 cells and transfected HEK293 cells and purification of TAL1 complexes for mass spectrometry were performed similarly as previously described 29 (see also supplemental Figure 5). …”

Section: Interaction Assaysmentioning

confidence: 99%

RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation

Kuvardina

Herglotz

Kolodziej

et al. 2015

Blood

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“…It has been proposed that PADIs could contribute to cancer by acting as coactivator of oncogenic transcription factors eliciting tumor-promoting expression programs. To illustrate this, PADI4 was shown to enhance transcriptional regulation of Tal1 in hematopoietic stem cells (17). However, the outcome of such a coactivator function is strongly dependent on the cellular context.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

Cantariño

Musulén

Valero

et al. 2016

Molecular Cancer Research

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Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is upregulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently, this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis.Implications: Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points toward a possible role of citrullination in modulating tumor cells and their microenvironment.

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“…It has been suggested that PADI4 may target different histone arginines (32,33). Kolodziej et al previously identified PADI4 as a novel interaction partner of T-cell acute lymphocytic leukemia protein 1 (Tal1), which is a critical regulator of hematopoietic gene expression and may act as an oncogene if aberrantly expressed, and identified a large number of genes that are co-regulated by PADI4 and Tal1 (31). Overexpression of PADI4 is often observed in growth of tumors, and the inhibitor Cl-amidine reduces growth of a subset of cell lines (34).…”

Section: Decreased Expression Normal Expression Overexpression ------mentioning

confidence: 99%

“…Yao et al reported that there is an inverse correlation between the expression of Bmi-1 and p14ARF, and thereby dysfunction of the p53 growth regulatory pathway during the development of gastric cardia adenocarcinoma (42). In addition, a number of studies proposed that PADI4 plays an important role in various cellular processes, including proliferation, the cell cycle and apoptosis (27,(30)(31)(32)(33). PADI4 overexpression has also been considered to reduce the expression of p53-targeted genes, resulting in the disruption of cellular apoptosis and of the normal cell cycle (35,43,44).…”

Section: Decreased Expression Normal Expression Overexpression ------mentioning

confidence: 99%

B-cell specific Moloney leukemia virus insert site 1 and peptidyl arginine deiminase IV positively regulate carcinogenesis and progression of esophageal squamous cell carcinoma

Wang¹,

Ji²,

Sun³

et al. 2017

Oncology Letters

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Abstract. High expression of B-cell specific Moloney leukemia virus insert site 1 (Bmi-1) and peptidyl arginine deiminase IV (PADI4) is associated with esophageal carcinoma. However, few studies have investigated the association between the Bmi-1 and PADI4 genes. The aim of the present study was to evaluate the expression of Bmi-1 and PADI4 and identify the association between the Bmi-1 and PADI4 genes in esophageal squamous cell carcinoma (ESCC) tissues. Bmi-1 and PADI4 gene expression levels were measured using immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction in ESCC tissues from 86 patients who had not received pre-operative chemoradiation. The results revealed that the Bmi-1 and PADI4 genes had increased expression in carcinoma tissues compared with pericarcinous tissue (P<0.05). Bmi-1 gene expression was revealed to be associated with differentiation degree, clinical stage and lymph node metastasis (P<0.05), but had no association with gender, age or depth of invasion (P>0.05). The expression of PADI4 was associated with clinical stage, depth of invasion and lymph node metastasis (P<0.05), but was not associated with gender, age or differentiation degree (P>0.05). In addition, there was a positive association between Bmi-1 and PADI4 gene expression in ESCC (P<0.05). These results indicated that Bmi-1 and PADI4 positively regulate carcinogenesis and progression of ESCC.

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PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation

Cited by 59 publications

References 69 publications

RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation

RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

B-cell specific Moloney leukemia virus insert site 1 and peptidyl arginine deiminase IV positively regulate carcinogenesis and progression of esophageal squamous cell carcinoma

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