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MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167478 | GEO | 2022/08/10

REPOSITORIES: GEO

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MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

Project description:We performed HIF-1alpha ChIP-seq in SK-N-BE(2) cells cultured in normoxia vs. hypoxia for 48 hrs. We identified two new HIF-1alpha binding sites in TET1 that control TET1expression in hypoxia

2022-08-10 | GSE167477 | GEO

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

Project description:We performed RNA-sequencing on inducible MYCN cell line SHEPTET21n on Day 4 post MYCN induction

2022-08-10 | GSE167476 | GEO

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

Project description:We characterized genome-wide 5-hydroxymerhylcytosine (5-hmC) distribution at 0,6,12,24, 48, 72 hours in hypoxia in SK-N-BE(2) neuroblastoma cell line.5-hmC increases over time in hypoxic but especially between 0 and 6 and 24 to 48 hours.

2022-08-10 | GSE167475 | GEO

MYCN and HIF-1 directly regulate <i>TET1</i> expression to control 5-hmC gains and enhance neuroblastoma cell migration in hypoxia.

Project description:Ten-Eleven-Translocation 5-methylcytosine dioxygenases 1-3 (TET1-3) convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), using oxygen as a co-substrate. Contrary to expectations, hypoxia induces 5-hmC gains in MYCN-amplified neuroblastoma (NB) cells via upregulation of TET1. Here, we show that MYCN directly controls TET1 expression in normoxia, and in hypoxia, HIF-1 augments TET1 expression and TET1 protein stability. Through gene-editing, we identify two MYCN and HIF-1 binding sites within TET1 that regulate gene expression. Bioinformatic analyses of 5-hmC distribution and RNA-sequencing data from hypoxic cells implicate hypoxia-regulated genes important for cell migration, including CXCR4. We show that hypoxic cells lacking the two MYCN/HIF-1 binding sites within TET1 migrate slower than controls. Treatment of MYCN-amplified NB cells with a CXCR4 antagonist results in slower migration under hypoxic conditions, suggesting that inclusion of a CXCR4 antagonist into NB treatment regimens could be beneficial for children with MYCN-amplified NBs.

| S-EPMC9665154 | biostudies-literature

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

| PRJNA704703 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

| PRJNA704701 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

| PRJNA704704 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

| PRJNA704705 | ENA

HIF-1 directly induces TET3 expression to enhance 5-hmC density and induce erythroid gene expression in hypoxia.

Project description:In mammalian cells, cytosines found within cytosine guanine dinucleotides can be methylated to 5-methylcytosine (5-mC) by DNA methyltransferases and further oxidized by the Ten-eleven translocation dioxygenase (TET) enzymes to 5-hydroxymethylcytosine (5-hmC). We have previously shown that hematopoietic stem and progenitor cells (HSPCs) with TET2 mutations have aberrant 5-hmC distribution and less erythroid differentiation potential. However, these experiments were performed under standard tissue culture conditions with 21% oxygen (O2), whereas HSPCs in human bone marrow reside in ∼1% O2. Therefore, to model human erythropoiesis more accurately, we compared 5-hmC distribution and gene expression in hypoxic vs normoxic conditions. Despite TET enzymes having limited O2 as a substrate in hypoxia, 5-hmC peaks were more numerous and pronounced than in normoxia. Among the TET genes, TET3 was upregulated specifically in hypoxia. We identified 2 HIF-1 binding sites in TET3 by chromatin immunoprecipitation of HIF-1α followed by sequencing, and TET3 upregulation was abrogated with deletion of both sites, indicating that TET3 is a direct HIF-1 target. Finally, we showed that loss of one or both of these HIF-1 binding sites in K562 cells disrupted erythroid differentiation in hypoxia and lowered cell viability. This work provides a molecular link between O2 availability, epigenetic modification of chromatin, and erythroid differentiation.

| S-EPMC7362358 | biostudies-literature

ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma.

Project description:Human anaplastic lymphoma kinase (ALK) has been identified as an oncogene that is mutated or amplified in NBLs. To obtain a better understanding of the molecular events associated with ALK in the pathogenesis of NBL, it is necessary to clarify how ALK gene contributes to NBL progression. In the present study, we found that ALK expression was significantly high in NBL clinical samples with amplified MYCN (n = 126, P < 0.01) and in developing tumors of MYCN-transgenic mice. Indeed, promoter analysis revealed that ALK is a direct transcriptional target of MYCN. Overexpression and knockdown of ALK demonstrated its function in cell proliferation, migration and invasion. Moreover, treatment with an ALK inhibitor, TAE-684, efficiently suppressed such biological effects in MYCN amplified cells and tumor growth of the xenograft in mice. Our present findings explore the fundamental understanding of ALK in order to develop novel therapeutic tools by targeting ALK for aggressive NBL treatment.

| S-EPMC3868972 | biostudies-literature

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