The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224886 | GEO | 2023/05/05
REPOSITORIES: GEO
Similar Datasets
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.
2023-05-05 | GSE224885 | GEO
Project description: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.
2023-05-05 | GSE224887 | GEO
Project description:Melanoma is a type of skin cancer that develops in pigment-producing melanocytes and often spreads to other parts of the body. Aberrant gene expression has been considered as a crucial step for increasing the risk of melanomagenesis, but how chromatin reorganization contributes to this pathogenic process is still not well understood. Here we report that matrix metalloproteinase 9 (MMP-9) localizes to the nucleus of melanoma cells and potentiates gene expression by proteolytically clipping histone H3 N-terminal tail (H3NT). From genome-wide studies, we discovered that growth regulatory genes are selectively targeted and activated by MMP-9-dependent H3NT proteolysis in melanoma cells. MMP-9 cooperates functionally with p300/CBP, because MMP-9 cleaves H3NT in a manner that is dependent on p300/CBP-mediated acetylation of H3K18. The functional significance of MMP-9-dependent H3NT proteolysis is further underscored by the fact that RNAi knockdown and small-molecule inhibition of MMP-9 and p300/CBP impede melanomagenic gene expression and melanoma tumor growth. Together, our data establish new functions and mechanisms for nuclear MMP-9 in promoting melanomagenesis and demonstrate how MMP-9-dependent H3NT proteolysis can be exploited to prevent and treat melanoma skin cancer.
2021-11-17 | GSE179367 | GEO
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.
2016-02-02 | GSE72957 | GEO
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.
2016-02-02 | GSE72846 | GEO
Project description:MMP-9 drives melanomagenic transcription program through histone H3 tail proteolysis
| PRJNA743353 | ENA
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.
2017-01-01 | GSE85597 | GEO
Project description:Invasive cancers employ pericellular proteolysis to breach the extracellular matrix and basement membrane barriers and invade the surrounding tissue. Pro-invasive, pro-tumorigenic MT1-MMP is the primary mediator of proteolytic events on the cancer cell surface. Cellular MT1-MMP is synthesized as a latent zymogen. The latency of MT1-MMP is maintained by its N-terminal inhibitory prodomain. Our study reveals a critical mechanism underlying the activation pathway and subsequent execution of the tumor-promoting function of MT1-MMP. Evidence suggests that the prodomain undergoes intradomain cleavage at the PGD↓L50 cleavage site followed by the release of the degraded prodomain by furin cleavage of the R108RKR111↓Y112 site. These events, only if combined, cause the activation of MT1-MMP. The significance of these molecular events to the pro-tumorigenic function of MT1-MMP in malignancy remained, however, unidentified. To identify the functional importance of the PGD↓L50 intradomain cleavage in the activation and tumorigenic program of MT1-MMP, our current studies employed the cells which expressed the wild-type prodomain-based fluorescent biosensor and the mutant biosensor with the inactivated PGD↓L50 cleavage site (L50D mutant) and also the cells with the enforced expression the wild-type and mutant MT1-MMP. Using cell-based tests and orthotopic breast cancer xenografts in mice, we demonstrated that the intradomain cleavage of the PGD↓L50 sequence of the prodomain is essential for the pro-tumorigenic function of MT1-MMP. Our study contributes to the growing consensus for the design of selective, precisely focused MT1-MMP inhibitors in cancer. Analysis of global gene expression in orthotopic tumor and cultured breast cancer cells expressing wild-type and mutant Mt1-MMP forms
2011-06-01 | E-GEOD-28655 | biostudies-arrayexpress
Project description:Invasive cancers employ pericellular proteolysis to breach the extracellular matrix and basement membrane barriers and invade the surrounding tissue. Pro-invasive, pro-tumorigenic MT1-MMP is the primary mediator of proteolytic events on the cancer cell surface. Cellular MT1-MMP is synthesized as a latent zymogen. The latency of MT1-MMP is maintained by its N-terminal inhibitory prodomain. Our study reveals a critical mechanism underlying the activation pathway and subsequent execution of the tumor-promoting function of MT1-MMP. Evidence suggests that the prodomain undergoes intradomain cleavage at the PGD↓L50 cleavage site followed by the release of the degraded prodomain by furin cleavage of the R108RKR111↓Y112 site. These events, only if combined, cause the activation of MT1-MMP. The significance of these molecular events to the pro-tumorigenic function of MT1-MMP in malignancy remained, however, unidentified. To identify the functional importance of the PGD↓L50 intradomain cleavage in the activation and tumorigenic program of MT1-MMP, our current studies employed the cells which expressed the wild-type prodomain-based fluorescent biosensor and the mutant biosensor with the inactivated PGD↓L50 cleavage site (L50D mutant) and also the cells with the enforced expression the wild-type and mutant MT1-MMP. Using cell-based tests and orthotopic breast cancer xenografts in mice, we demonstrated that the intradomain cleavage of the PGD↓L50 sequence of the prodomain is essential for the pro-tumorigenic function of MT1-MMP. Our study contributes to the growing consensus for the design of selective, precisely focused MT1-MMP inhibitors in cancer.
2011-06-01 | GSE28655 | GEO
Project description:MT1-MMP and MT2-MMP double deficiency in mice leads to development of a placental defect resulting in embryonic death after E10.5. The protein substrate for these two proteases in placenta is unknown, which poses an obstacle in uncovering of molecular mechanism behind the observed placental defect. In search for a potential substrate for these two proteases in placenta we have employed whole genome microarray expression profiling as a discovery platform to identify genes, expression of which might be affected by double MMP deficiency. Fetal parts of mouse placentas were isolated from E10.5 placentas of different genotypes for MT1- and MT2-MMP.
2010-03-09 | E-GEOD-18604 | biostudies-arrayexpress