Identification of genome-wide targets of acetylated NPM1 (AcNPM1) mediated transcriptional regulation.
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ABSTRACT:
PROVIDER: PRJNA549267 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9310770_1.fastq.gz | Fastqsanger.gz | |||
| SRR9310770_2.fastq.gz | Fastqsanger.gz | |||
| SRR9310771_1.fastq.gz | Fastqsanger.gz | |||
| SRR9310771_2.fastq.gz | Fastqsanger.gz | |||
| SRR9310772_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the first genome-wide profile of AcNPM1 occupancy in HeLa S3 cells by performing ChIP-sequencing using a AcNPM1 specific antibody. We show that AcNPM1 is associated with active transcription. AcNPM1 occupies transcriptional regulatory elements such as promoters and enhancers through its interaction with RNA Polymerase II, general transcription factors, transcription factors as well as histone acetyltransferases and chromatin remodeling complexes. Using RNA-sequencing afer NPM1 knockdown in oral cancer cell line AW13516, we also show that AcNPM1 regulates key pathways associated with cell proliferation, migration and invasion.
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Project description:Mutation in the nucleophosmin (NPM1) gene is frequent in acute myeloid leukemia (AML). This mutation has remarkable prognostic significance and correlates with distinct biological features. Our data from the sample-paired microRNA (miRNA) and mRNA microarrays of de novo AML patients strongly indicated that miRNAâmRNA regulation (MMR) may be dynamic and can be modulated by NPM1 mutation. We identified 493 NPM1 mutation-modulated MMR pairs by a systematic framework, in which MMR was attenuated specifically in patients carrying NPM1 mutations. The involved miRNAs/mRNAs were associated with cancer and hematological diseases, as well as known functions of NPM1 mutation including cell death and cellular response to therapeutics. The NPM1 mutation modulation could be validated with three approaches, including two independent cohort datasets, a high-throughput dataset derived from cell line-based experiments, and two in vitro models. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which novel prognostic markers are derived in AML. Cryopreserved bone marrow cells were obtained from 109 de novo AML patients. Each sample was analyzed with Illumina HumanHT-12 V4.0 expression beadchip.
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Project description:Mutation in the nucleophosmin (NPM1) gene is frequent in acute myeloid leukemia (AML). This mutation has remarkable prognostic significance and correlates with distinct biological features. Our data from the sample-paired microRNA (miRNA) and mRNA microarrays of de novo AML patients strongly indicated that miRNAâmRNA regulation (MMR) may be dynamic and can be modulated by NPM1 mutation. We identified 493 NPM1 mutation-modulated MMR pairs by a systematic framework, in which MMR was attenuated specifically in patients carrying NPM1 mutations. The involved miRNAs/mRNAs were associated with cancer and hematological diseases, as well as known functions of NPM1 mutation including cell death and cellular response to therapeutics. The NPM1 mutation modulation could be validated with three approaches, including two independent cohort datasets, a high-throughput dataset derived from cell line-based experiments, and two in vitro models. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which novel prognostic markers are derived in AML. Cryopreserved bone marrow cells were obtained from 109 de novo AML patients. Each sample was analyzed with nCounter® Human miRNA Expression Array.
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Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function. Bone marrow derived dendritic cells were treated with SAHA (500 nm) or diluent for 12 hours. ChIP was performed using antibodies against STAT3, H3K4me3 and matched IgG control. DNA binding profiles were generated by deep sequencing using Illumina HiSeq 2000.
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Project description:Mutation in the nucleophosmin (NPM1) gene is frequent in acute myeloid leukemia (AML). This mutation has remarkable prognostic significance and correlates with distinct biological features. Our data from the sample-paired microRNA (miRNA) and mRNA microarrays of de novo AML patients strongly indicated that miRNA−mRNA regulation (MMR) may be dynamic and can be modulated by NPM1 mutation. We identified 493 NPM1 mutation-modulated MMR pairs by a systematic framework, in which MMR was attenuated specifically in patients carrying NPM1 mutations. The involved miRNAs/mRNAs were associated with cancer and hematological diseases, as well as known functions of NPM1 mutation including cell death and cellular response to therapeutics. The NPM1 mutation modulation could be validated with three approaches, including two independent cohort datasets, a high-throughput dataset derived from cell line-based experiments, and two in vitro models. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which novel prognostic markers are derived in AML.
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Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function.
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