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Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [RNA-seq]

ABSTRACT: Histone proteolysis is a poorly understood phenomena by which the N-terminal tail of histones are irreversible cleaved by intracellular proteases. During development histone PTMs are known orchestrate gene expression and ultimately cell fate decision, therefore it will be key to decipher underlying mechanisms that lead to proteolysis during cellular differentiation. Previous reports have found that histone H2A is cleaved at the C-terminus, and here we found that the N-terminal is also proteolytically clipped and removed by the lysosomal protease Cathepsin L. Using quantitative mass spectrometry (MS), we identified L23 to be the primary site for this protease, with this clipped H2A (cH2A) form representing ~1% of the total H2A reaching a maximum after 4 days of differentiation. Using Chip-seq, we found reduced proteolysis, lead to increase acetylated H2A at promoter regions in differentiated ES cells. We also report novel readers of acetylated H2A during in pluripotency as we identified members of the pBAF complex to recognize different forms of H2A acetylation. Moreover, our data showed that this recognition is abolished upon proteolysis. All in, our data suggest that proteolysis serve as a quick mechanism to silence genes involve in pluripotency and destabilize the nucleosome core particle as indicated by protein degradation studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE162877 | GEO | 2021/12/31

REPOSITORIES: GEO

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Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [ARID2 and PBRM1 ChIP-seq]

Project description:Histone proteolysis is a poorly understood phenomena by which the N-terminal tail of histones are irreversible cleaved by intracellular proteases. During development histone PTMs are known orchestrate gene expression and ultimately cell fate decision, therefore it will be key to decipher underlying mechanisms that lead to proteolysis during cellular differentiation. Previous reports have found that histone H2A is cleaved at the C-terminus, and here we found that the N-terminal is also proteolytically clipped and removed by the lysosomal protease Cathepsin L. Using quantitative mass spectrometry (MS), we identified L23 to be the primary site for this protease, with this clipped H2A (cH2A) form representing ~1% of the total H2A reaching a maximum after 4 days of differentiation. Using Chip-seq, we found reduced proteolysis, lead to increase acetylated H2A at promoter regions in differentiated ES cells. We also report novel readers of acetylated H2A during in pluripotency as we identified members of the pBAF complex to recognize different forms of H2A acetylation. Moreover, our data showed that this recognition is abolished upon proteolysis. All in, our data suggest that proteolysis serve as a quick mechanism to silence genes involve in pluripotency and destabilize the nucleosome core particle as indicated by protein degradation studies.

2022-03-22 | GSE196205 | GEO

Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation [H2AK9ac ChIP-seq]

2021-12-31 | GSE162874 | GEO

Targeted proteolysis of the histone H3 tail facilitates epigentic reporgramming 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 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

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

HIV-1 protease degradomics - Identify proteins cleaved during HIV-1 infection in an unbiased manner and on a proteome-wide scale

Project description:To identify proteins cleaved during HIV-1 infection in an unbiased manner and on a proteome-wide scale, positional proteomics was used to identify proteolysis-reporter peptides or so-called neo-N-terminal peptides. The spectra stored in this PRIDE experiment (n=148) are the highest scoring spectra of neo-N-terminal peptides generated by cleavage of recombinant HIV-1 protease added to a lysate of human Jurkat T-cells.

2012-08-07 | PRD000378 | Pride

Trypanosoma brucei histones are heavily modified with combinatorial post-translational modifications and mark Pol II transcription start regions with hyperacetylated H2A.

Project description:Trypanosomes diverged from the main eukaryotic lineage about 600 million years ago, and display some unusual genomic and epigenetic properties that provide valuable insight into the early processes employed by eukaryotic ancestors to regulate chromatin-mediated functions. We sequenced Trypanosoma brucei core histones by high mass accuracy middle-down mass spectrometry to map core histone post-translational modifications (PTMs) and elucidate cis histone combinatorial PTMs (cPTMs). T. brucei histones are heavily modified and display intricate cPTMs patterns, with numerous hypermodified cPTMs that could contribute to the formation of non repressive euchromatic states. The T. brucei H2A C terminal tail is hyperacetylated, containing up to 5 acetylated lysine residues. MNase-ChIP-seq revealed a striking enrichment of hyperacetylated H2A at Pol II transcription start regions, and showed that H2A histones that are hyperacetylated in different combinations localised to different genomic regions, suggesting distinct epigenetic functions. Our genomics and proteomics data provide insight into the complex epigenetic mechanisms used by this parasite to regulate a genome that lacks the transcriptional control mechanisms found in higher eukaryotes. The findings further demonstrate the complexity of epigenetic mechanisms that were probably shared with the last eukaryotic common ancestor.

2022-08-21 | PXD024574 | Pride

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

Trypanosoma brucei histones are heavily modified with combinatorial post-translational modifications and mark Pol II transcription start regions with hyperacetylated H2A.

Project description:Trypanosomes diverged from the main eukaryotic lineage about 600 million years ago, and display some unusual genomic and epigenetic properties that provide valuable insight into the early processes employed by eukaryotic ancestors to regulate chromatin-mediated functions. We sequenced Trypanosoma brucei core histones by high mass accuracy middle-down mass spectrometry to map core histone post-translational modifications (PTMs) and elucidate cis‑histone combinatorial PTMs (cPTMs). T. brucei histones are heavily modified and display intricate cPTMs patterns, with numerous hypermodified cPTMs that could contribute to the formation of non‑repressive euchromatic states. The T. brucei H2A C‑terminal tail is hyperacetylated, containing up to 5 acetylated lysine residues. MNase-ChIP-seq revealed a striking enrichment of hyperacetylated H2A at Pol II transcription start regions, and showed that H2A histones that are hyperacetylated in different combinations localised to different genomic regions, suggesting distinct epigenetic functions. Our genomics and proteomics data provide insight into the complex epigenetic mechanisms used by this parasite to regulate a genome that lacks the transcriptional control mechanisms found in higher eukaryotes. The findings further demonstrate the complexity of epigenetic mechanisms that were probably shared with the last eukaryotic common ancestor.

2021-01-19 | GSE165034 | GEO

Rat podocyte degradomics - N-Degradomic Analysis Reveals a Proteolytic Network Processing the Podocyte Cytoskeleton

Project description:Regulated intracellular proteolysis is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. Altered proteolytic substrate turnover has been associated with various glomerular diseases ranging from diabetic nephropathy to focal and segmental glomerulosclerosis. However, thus far it has not been possible to systematically identify proteolytically cleaved proteins although some of the proteases have been characterized. Here we applied TAILS to identify N-termini in rat glomeruli and their changes on PAN-induced injury.

2017-07-20 | PXD006356 | Pride

Middle-down MS analysis of intact and clipped histone H3 proteoforms

Project description:There is growing evidence that proteolytic cleavage of histone N-terminal tails, known as histone clipping, influences nucleosome dynamics and functional properties. Using middle-down MS analysis we characterized intact and proteolytically processed histone H3 proteoforms isolated from human hepatocarcinoma cell line HepG2/C3A grown in 3D culture.

2022-03-14 | PXD002535 | Pride

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