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The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Our study examines the role of MMP-2 mediated Histone H3NT proteolysis in U2OS cells. We find binding of MMP-2 at all active protein coding transcription start sites, and examine the role it plays in local chromatin regulation and changes in gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224887 | GEO | 2023/05/05

REPOSITORIES: GEO

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The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes [ChIP-seq]

Project description:Our study examines the role of MMP-2 mediated Histone H3NT proteolysis in U2OS cells. We find binding of MMP-2 at all active protein coding transcription start sites, and examine the role it plays in local chromatin regulation and changes in gene expression.

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The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes [RNA-seq]

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MMP-9 drives melanomagenic transcription program through histone H3 tail proteolysis

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MMP-9-dependent proteolysis of the histone H3 N-terminal tail, a critical epigenetic step in driving oncogenic transcription and colon tumorigenesis

Project description:The matrix metalloproteinase 9 (MMP-9) is a member of the MMP family and has been recently identified as a nuclear protease capable of clipping histone H3 N-terminal tails (H3NT). This MMP-9-dependent H3NT proteolysis is critical for establishing active state of gene transcription during osteoclast differentiation and melanoma development. However, whether H3NT cleavage by MMP-9 plays a similar role in other cellular events has not been explored. Here we dissect the functional contribution of MMP-9-dependent H3NT clipping to colonic tumorigenesis by using a combination of genome-wide transcriptome data, ChIP/ChIPac-qPCR, CRISPR/dCas9 gene-targeting system, and in vivo xenograft models. We show that MMP-9 is overexpressed in colon cancer cells and catalyzes H3NT proteolysis to drive transcriptional activation of growth stimulatory genes. Our studies using knockdown and inhibition approaches clearly indicate that MMP-9 mediates transcriptional activation and promote colonic tumorigenesis in a manner dependent on its protease activity toward H3NT. Remarkably, artificial H3NT proteolysis at target gene promoters with dCAS9-MMP-9 is sufficient for establishing their transcriptional competence in colon cancer cells, underscoring the importance of MMP-9-dependent H3NT proteolysis per se in transactivation process. Our data establish new functions and mechanisms for MMP-9 in driving oncogenic transcription program in colon cancer through H3NT proteolysis and demonstrate how this epigenetic pathway can be exploited as a potential therapeutic target for cancer treatment.

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Targeted proteolysis of the histone H3 tail facilitates epigenetic reprogramming during differentiation

Project description:Though limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, however the specific genomic sites targeted for H3NT proteolysis and their functional significance of H3NT cleavage remain unknown.We used genome wide Chip-seq (ChIPac-Seq) approaches to an established cell model of osteoclast differentiation. We discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most of these H3NT-cleaved genes are epigenetically regulated during osteoclastogenesis.We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9).Abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. In summary our results support the necessity of MMP-9-dependent H3NT proteolysis in the epigenetic reprogramming of gene pathways required for proficient osteoclastogenesis.

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Project description:Though limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, however the specific genomic sites targeted for H3NT proteolysis and their functional significance of H3NT cleavage remain unknown.We used genome wide RNA-seq approaches to an established cell model of osteoclast differentiation. We discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most of these H3NT-cleaved genes are epigenetically regulated during osteoclastogenesis.We have identified that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). We next studied genomewide mRNA expression in MMP9 knockout cells and its effect in the epigenetic reprogramming of gene pathways required for proficient osteoclastogenesis.

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The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

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Extracellular Matrix Proteolysis by MT1-MMP is Associated with Influenza-Related Mortality

Project description:The balance between protecting tissue integrity and efficient immune response is critical for host survival. Here we investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection using a combined genomic and proteomic approach. We followed the transcriptional dynamics and ECM- related responses in a mouse model of influenza virus infection, integrated with whole tissue imaging and functional assays. Our study identifies MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza virus infection. We show that selective inhibition of MT1-MMP-driven ECM proteolysis protects the tissue from infection-related structural and compositional damage. Inhibition of MT1-MMP did not significantly alter the immune response or cytokine expression, indicating its dominant role in ECM remodeling. We demonstrate that the available treatment for influenza virus (Tamiflu/ Oseltamivir) does not prevent lung ECM damage and is less effective than anti-MT1-MMP treatment in influenza virus and Streptococcus pneumoniae coinfection paradigms. Importantly, combination therapy of Tamiflu with anti-MT1-MMP shows a strong synergistic effect and results in complete recovery in mice. This study highlights the importance of tissue tolerance agents for surviving infectious diseases, and the potential of such host-pathogen therapy combination for respiratory infections.

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The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes [RNA-seq]

Project description:The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes [RNA-seq]

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