Activator protein transcription factors coordinate human IL-33 expression from non-canonical promoters in chronic airway disease
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ABSTRACT:
PROVIDER: PRJNA1050232 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27148418_1.fastq.gz | Fastqsanger.gz | |||
| SRR27148418_2.fastq.gz | Fastqsanger.gz | |||
| SRR27148419_1.fastq.gz | Fastqsanger.gz | |||
| SRR27148419_2.fastq.gz | Fastqsanger.gz | |||
| SRR27148420_1.fastq.gz | Fastqsanger.gz |
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Project description:Interleukin-33 (IL-33) is a cytokine central to type-2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how this is regulated is undefined. Here we show IL-33 is expressed from multiple promoters in human chronic obstructive pulmonary disease (COPD) and non-canonical promoters mediate production of alternatively spliced isoforms. Transposase-accessible chromatin sequencing (ATAC-seq) performed on cell lines with distinct IL-33 expression levels demonstrated chromatin accessibility as a control point for IL-33 expression. We further discovered that phorbol esters activate non-canonical IL-33 promoters through protein kinase C in airway cells. Transcription factor (TF) binding arrays combined with RNA interference revealed Activator Protein transcription factors as the downstream effectors of non-canonical IL-33 promoter activation. In support of a role for Activator Protein-2 family members in COPD pathogenesis, we found both TFAP2A and TFAP2C are upregulated in disease, with phosphorylated TFAP2C localized to IL-33-positive airway basal cells in COPD lung tissue. This study defines how pioneer transcription factors associated with stemness can drive non-canonical IL-33 promoters and alternative splicing patterns in airway epithelial progenitors. Our work reveals a novel approach for targeting the IL-33 pathway to promote the development of new therapeutics for COPD.
2024-04-03 | GSE249720 | GEO
Project description:IL-33 is a cytokine central to type 2 immune pathology in chronic airway disease. This cytokine is abundantly expressed in the respiratory epithelium and increased in disease, but how expression is regulated is undefined. Here we show that increased IL33 expression occurs from multiple noncanonical promoters in human chronic obstructive pulmonary disease (COPD), and it facilitates production of alternatively spliced isoforms in airway cells. We found that phorbol 12-myristate 13-acetate (PMA) can activate IL33 promoters through protein kinase C in primary airway cells and lines. Transcription factor (TF) binding arrays combined with RNA interference identified activator protein (AP) TFs as regulators of baseline and induced IL33 promoter activity. ATAC-Seq and ChIP-PCR identified chromatin accessibility and differential TF binding as additional control points for transcription from noncanonical promoters. In support of a role for these TFs in COPD pathogenesis, we found that AP-2 (TFAP2A, TFAP2C) and AP-1 (FOS and JUN) family members are upregulated in human COPD specimens. This study implicates integrative and pioneer TFs in regulating IL33 promoters and alternative splicing in human airway basal cells. Our work reveals a potentially novel approach for targeting IL-33 in development of therapeutics for COPD.
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Project description:The position of nucleosomes influences DNA accessibility to DNA-binding proteins. Genome-wide nucleosome profiles often report the observation of a canonical nucleosome organization at gene promoters where arrays of well-positioned nucleosomes emanate from nucleosome-depleted regions. It is unclear how this canonical promoter nucleosome organization forms and how it is related to transcription activation and the establishment of histone marks during development. Here we report the genome-wide organization of nucleosomes during zebrafish embryogenesis and show that well-positioned nucleosome arrays appear in thousands of promoters during the activation of the zygotic genome. The formation of canonical promoter nucleosome organization cannot be explained by DNA sequence preference, and is independent of transcription and the presence of RNA polymerase II, but strongly correlates with the presence of Histone H3 Lysine 4 trimethylation (H3K4me3). Our study further suggests that promoter nucleosome structure primes genes to future transcription activation. Together, this study reveals that genome activation but not transcription underlies the organization of nucleosome arrays during early embryogenesis. MNase-seq to generate nucleosome organization in two stages of zebrafish development; two biological replicates for each stage. 7 ChIP-seq experiments in three stages.
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Project description:Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells
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Project description:The organization of nucleosomes influences transcriptional activity by controlling accessibility of DNA binding proteins to the genome. Genome-wide nucleosome binding profiles have identified a canonical nucleosome organization at gene promoters, where arrays of well-positioned nucleosomes emanate from nucleosome-depleted regions. The mechanisms of formation and the function of canonical promoter nucleosome organization remain unclear. Here we analyze the genome-wide location of nucleosomes during zebrafish embryogenesis and show that well-positioned nucleosome arrays appear on thousands of promoters during the activation of the zygotic genome. The formation of canonical promoter nucleosome organization is independent of DNA sequence preference, transcriptional elongation, and robust RNA polymerase II (Pol II) binding. Instead, canonical promoter nucleosome organization correlates with the presence of Histone H3 Lysine 4 trimethylation (H3K4me3) and affects future transcriptional activation. These findings reveal that genome activation is central to the organization of nucleosome arrays during early embryogenesis.
2013-10-18 | GSE44269 | GEO
Project description:The organization of nucleosomes influences transcriptional activity by controlling accessibility of DNA binding proteins to the genome. Genome-wide nucleosome binding profiles have identified a canonical nucleosome organization at gene promoters, where arrays of well-positioned nucleosomes emanate from nucleosome-depleted regions. The mechanisms of formation and the function of canonical promoter nucleosome organization remain unclear. Here we analyze the genome-wide location of nucleosomes during zebrafish embryogenesis and show that well-positioned nucleosome arrays appear on thousands of promoters during the activation of the zygotic genome. The formation of canonical promoter nucleosome organization is independent of DNA sequence preference, transcriptional elongation, and robust RNA polymerase II (Pol II) binding. Instead, canonical promoter nucleosome organization correlates with the presence of Histone H3 Lysine 4 trimethylation (H3K4me3) and affects future transcriptional activation. These findings reveal that genome activation is central to the organization of nucleosome arrays during early embryogenesis.
2013-10-29 | GSE51766 | GEO
Project description:Transcription in eukaryotes correlates with major chromatin changes, including the replacement of old nucleosomal histones by new histones at the promoters of genes. The role of these histone exchange events in transcription remains unclear. In particular, the causal relationship between histone exchange and activator binding, preinitiation complex (PIC) assembly, and/or subsequent transcription remains unclear. Here, we provide evidence that histone exchange at gene promoters is not simply a consequence of PIC assembly or transcription but instead is mediated by activators. We further show that not all activators up-regulate gene expression by inducing histone turnover. Thus, histone exchange does not simply correlate with transcriptional activity, but instead reflects the mode of action of the activator. Last, we show that histone turnover is not only associated with activator function but also plays a role in transcriptional repression at the histone loci.
2020-01-09 | GSE143305 | GEO
Project description:The Set2-Rpd3S pathway is important for the control of transcription memory. Mutation of components of this pathway results in cryptic transcription initiation within the coding region of approximately 30% of yeast genes. Specifically, deletion of the Set2 histone methyltransferase or Rco1, a component of the Rpd3S histone deacetylase complex leads to hyperacetylation of certain open reading frames (ORFs). We used this mutant as a system to study the role of histone modifications and co-activator recruitment in preinitiation complex (PIC) formation. Specifically, we looked at the dependence of promoters on the bromodomain-containing RSC complex and the Bdf1 protein. We found that the dependence of cryptic promoters for these proteins varied. Overall, our data indicates that cryptic promoters are independently regulated, and their activation is dependent on factors that govern gene activation at canonical promoters. Two-sample experiment: chromatin immunoprecipitation (ChIP) sample vs. input. Biological replicates: 3 independent ChIP samples for each yeast strain.
2010-09-23 | E-GEOD-17521 | biostudies-arrayexpress
Project description:Histone Exchange is Associated with Activator Function at Transcribed Promoters and with Repression at Histone Loci
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Project description:The Set2-Rpd3S pathway is important for the control of transcription memory. Mutation of components of this pathway results in cryptic transcription initiation within the coding region of approximately 30% of yeast genes. Specifically, deletion of the Set2 histone methyltransferase or Rco1, a component of the Rpd3S histone deacetylase complex leads to hyperacetylation of certain open reading frames (ORFs). We used this mutant as a system to study the role of histone modifications and co-activator recruitment in preinitiation complex (PIC) formation. Specifically, we looked at the dependence of promoters on the bromodomain-containing RSC complex and the Bdf1 protein. We found that the dependence of cryptic promoters for these proteins varied. Overall, our data indicates that cryptic promoters are independently regulated, and their activation is dependent on factors that govern gene activation at canonical promoters.
2010-09-23 | GSE17521 | GEO