PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1143570 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30117027_1.fastq.gz | Fastqsanger.gz | |||
| SRR30117027_2.fastq.gz | Fastqsanger.gz | |||
| SRR30117028_1.fastq.gz | Fastqsanger.gz | |||
| SRR30117028_2.fastq.gz | Fastqsanger.gz | |||
| SRR30117029_1.fastq.gz | Fastqsanger.gz |
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Project description:HIV-1 infection establishes a reservoir of long-lived cells with integrated proviral DNA that can persist despite antiretroviral therapy (ART). The mechanisms governing the transcriptional regulation of the provirus are complex and incompletely understood. Here, we investigated the role of histone H3 citrullination, a post-translational modification catalyzed by protein-arginine deiminase type-4 (PADI4), in HIV-1 transcription and latency. We found that PADI4 inhibition by GSK484 reduced HIV-1 transcription after T cell activation in ex vivo cultures of CD4 T cells from viremic and ART treated people living with HIV-1 (PLWH). The effect was more pronounced in the viremic group. Using cell models of HIV-1 latency, we showed that PADI4-mediated citrullination of histone H3 occurred at the HIV-1 promoter upon T cell stimulation which facilitated proviral transcription. HIV-1 preferentially integrated into genomic regions marked by H3 citrullination and these integrated proviruses were less prone to latency compared to those in non-citrullinated chromatin. Inhibiting PADI4 led to compaction of the HIV-1 promoter chromatin and an increase of HP1a-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism of HIV-1 transcriptional regulation by PADI4 through H3 citrullination.
2024-08-05 | GSE273899 | GEO
Project description:Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline residues on histone tails. This activity has been linked to the repression of gene transcription on a limited number of genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 cells. Results showed that PADI4 is enriched in the gene promoter regions near the transcription start sites (TSSs) and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. The expression of two well characterized Elk-1 target genes, c-fos and egr-1, was then found to be inhibited following treatment of MCF-7 cells with a PADI4 specific inhibitor. The inhibitor also significantly reduced levels of acetylation at H4 lysine 5 at these promoters suggesting that the activating function of PADI4 at these target genes is mediated, in part, by interplay between histone citrullination and HAT-mediated acetylation. These findings greatly expand our knowledge of the role of PADI4 in gene regulation by defining a new role for PADI4 catalyzed histone citrullination in mediating gene transactivation. Two PADI4 ChIP-chip biological replicates from MCF-7 human breast cancer cells are included.
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Project description:Citrullination refers to the conversion of arginine into the non-essential amino acid citrulline. Despite its importance in physiology and disease, global identification of citrullinated proteins and modification sites has remained challenging. Here, we combined quantitative mass spectrometry-based proteomics with differentiation of a leukemia cell line into neutrophil-like cells to reveal a comprehensive atlas of citrullination sites. Collectively, we identified 14.056 citrullination sites within 4.008 proteins and quantified their regulation in response to PADI4-specific inhibitor GSK484. Hereby we uncovered general principles about the mechanistic and biological aspects of citrullination function, while providing site-specific and quantitative regulation of thousands of PADI4 substrates, including signature histone marks and numerous non-histone events on transcriptional regulators and chromatin-related signaling effectors. Collectively, we describe systems attributes of the human citrullinome, reveal the existence of thousands citrullinated autoantigens in neutrophil cells, and provide a resource framework for investigating PADI4-specific functions and substrates for years to come.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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Project description:TP53 encodes for the transcription factor p53, which binds to a diverse set of target genes in response to stress. Activation of p53 results in highly specific transcriptional responses, but the regulation of promoter selectivity by p53 is poorly understood. Here we report that sequence-specific binding of p53 is regulated by its target gene and binding partner PADI4. PADI4 enzymatically converts peptidyl-arginine to peptidyl-citrulline in a process known as citrullination. We show p53 is citrullinated in vitro at the C-terminus by PADI4, and we confirm two citrullination events in vivo (R306, R363). ChIP-seq reveals that PADI4 expression causes a redirection of p53 away from canonical binding sites to target genes associated with the ETS transcription factor and the interferon response. Chromatin profiling using citrullination-specific p53 antibodies supports this conclusion. These findings link citrullination to p53 function and illustrate how chromatin modifiers like PADI4 can redirect the p53 transcriptional response.
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