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PATZ1 is a DNA damage responsive transcription factor that inhibits p53 function [doxorubicin treatment]

ABSTRACT: Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE71529 | GEO | 2017/07/29

SECONDARY ACCESSION(S): PRJNA291437

REPOSITORIES: GEO

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PATZ1 is a DNA damage responsive transcription factor that inhibits p53 function

Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway. RNA-seq was used to define differentially expressed genes in wild-type and PATZ1-/- MEFs. Each sample was represented in triplicate.

2015-03-27 | E-GEOD-65864 | biostudies-arrayexpress

PATZ1 is a DNA damage responsive transcription factor that inhibits p53 function

2015-03-27 | GSE65864 | GEO

PATZ1 ChIP-Seq

Project description:Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma HepG2 cells. PATZ1 level was found to be ectopically expressed in hepatocellular carcinoma cells compared to normal primary human hepatocytes, thus affirming its relevance in liver cancer. Our gene expression microarray and PATZ1 ChIP-seq analysis further revealed strong enrichment in gene ontology terms related to cellular proliferation. Importantly, siRNA-mediated PATZ1 knockdown in HepG2 cells led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Furthermore, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its promoter activity. Additionally, we found that PATZ1 associates with p53 and the absence of p53 abrogated the PATZ1-mediated regulation of CDKN1B expression. In conclusion, our study provides novel mechanistic insights into the role of PATZ1 in liver cancer progression, thereby providing a promising therapeutic intervention to alleviate tumor burden in liver cancer.

2020-12-31 | GSE114030 | GEO

Genome-wide expression of PATZ1 knockdown in HepG2 cells

2020-12-31 | GSE113859 | GEO

PATZ1 ChIP-Seq

Project description:PATZ1 ChIP-Seq

| PRJNA462436 | ENA

PATZ1-knockdown expression array and PATZ1 ChIP-seq in HepG2 cells

Project description:PATZ1-knockdown expression array and PATZ1 ChIP-seq in HepG2 cells

| PRJNA459529 | ENA

Expression analysis of WT and Zbtb4 -/- mouse primary fibroblasts

Project description:ZBTB4 is a mammalian transcription factor with Zinc fingers and a BTB/POZ domain, which can bind methylated CpGs, as well as certain unmethylated consensus sequences. ZBTB4 is frequently downregulated in human cancers, but it is unclear whether this is a cause or consequence of transformation. To investigate the role of ZBTB4 in normal and pathological conditions, we generated Zbtb4-/- mice

2016-11-10 | GSE77816 | GEO

Gene expression in mature CD4 and CD8 from WT mice and mature CD4 from DBTBLZ or Mta2-DBTBLZ retrogenic mice

Project description:T cell precursors develop into cytotoxic CD8 and helper CD4+ T cells in thymus. Thpok, a BTB/POZ family transcription factor, enforces commitment to the CD4 lineage and suppresses cytotoxic gene expression. However, it is still not fully understood how Thpok directs CD4 T cell development. Here, using mass-spectrometry, we identify nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We demonstrate that the Thpok BTB domain is essential for NuRD recruitment. Reconstituting NuRD binding to a BTB-less version of Thpok (which cannot bind NuRD) restored CD4 T cell in vivo. RNA sequencing showed that CD4 T cells expressing the reconstituted protein express a transcriptome similar to that of CD4 T cells expressing Thpok. Thus, our results demonstrate that NuRD recruitment is both necessary and sufficient for the function of the Thpok BTB domain in CD4 T cell development.

2022-06-10 | GSE171610 | GEO

Expanding the spectrum of CNS EWSR1-PATZ1 rearranged tumors: an infantile case with leptomeningeal dissemination

Project description:This case shows similarities with 2 previously reported cases, including intraventricular location, histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and immunophenotype with co-expression of OLIG2, GFAP and synaptophysin. The onset in an infant, the presence of a high-grade component and the leptomeningeal dissemination, however, have not been previously reported in EWSR1-PATZ1 rearranged tumors, expanding the clinico-pathological spectrum.

2020-12-03 | GSE162537 | GEO

RNA-Seq analysis of T-ALL mouse samples and the effect of Miz1 POZ domain deletions on T-ALL expression profiles

Project description:T cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease mainly affecting children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage cause health problems later in life, underlining the need for improved therapies. We show that ablation of the BTB/POZ domain factor Miz-1 significantly delays Notch1-induced T-ALL in mice through induction of p53-dependent cell death. Leukemic cells that still emerge in this system activate DNA replication and strand elongation pathways, which are those targeted by current chemotherapeutic drugs such as cytarabine. Acute Miz-1 ablation enhances the effect of cytarabine treatment and eliminates leukemic cells completely in some cases, suggesting that targeting Miz-1 could render current T-ALL chemotherapies more effective.

2020-01-01 | GSE95395 | GEO

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