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Targeted proteolysis of the histone H3 tail facilitates epigentic reporgramming during differentiation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE72846 | GEO | 2016/02/02

SECONDARY ACCESSION(S): PRJNA295187

REPOSITORIES: GEO

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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.

2016-02-02 | GSE72957 | GEO

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

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

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.

2023-05-05 | GSE224886 | GEO

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

2023-05-05 | GSE224885 | GEO

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

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

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

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

| PRJNA743353 | ENA

A functional map of DNA-associated proteolysis

Project description:We established an assay to localize DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map we describe here ties proteolysis to active enhancer elements and to transcription start sites of specific gene families. ChIP-sequencing of ubiquitin and transcription factors was performed in the presence or absence of proteasome inhibition.

2013-12-01 | E-GEOD-33821 | biostudies-arrayexpress

A functional map of DNA-associated proteolysis

2013-12-01 | GSE33821 | GEO

Repurposing E3 ubiquitin ligases as cell surface protein degraders using Proteolysis Targeting Antibodies

Project description:The majority of current therapeutics targeting plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. Typical mammalian proteins, however, consist of multiple domains executing discrete but coordinated activities, and saturating inhibition of one functional domain often incompletely suppresses the totality of the protein’s function. Recent work on targeted protein degradation technologies including Proteolysis Targeting Chimeras (PROTACs) has highlighted clinically important distinctions between target inhibition and target degradation. However, the generation of heterobifunctional compounds requiring linkage of two small molecules, each with high affinity for their targets, is highly complex, particularly with respect to achieving oral bioavailability. Here we describe the development of Proteolysis Targeting Antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target ubiquitination and subsequent degradation. PROTAB-mediated degradation drives deeper pathway inhibition than inhibitory antibodies and is functional in vivo. The scope of this technology is also demonstrated through the identification of additional cell surface E3 ubiquitin ligases that can function as “on demand” degraders of various cell surface proteins. The generality of this approach enables tissue-selective degradation, as suggested by the Wnt-responsive ligases RNF43 and ZNRF3. Furthermore, through engineering of various optimized antibody formats, we offer insights on the ground rules governing optimal target degradation. Taken together, this work describes a strategy for the rapid development of potent, bioavailable and tissue selective degradation of cell surface proteins.

2022-07-21 | GSE208372 | GEO

Expression of RAW264.7 cells stimulated with RANKL and treated with supernatant from Lactobacillus reuteri

Project description:Analysis of gene expression in RAW264.7 cells stimulated for osteoclastogenesis and then treated with cell culture supernatant from Lactobacillus reuteri. Results will offer insight into targeted mechanisms suppressing osteoclastogenesis

2019-08-13 | GSE135755 | GEO

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