Tryptase-catalyzed core histone truncation: A novel epigenetic regulatory mechanism in mast cells

Melo, Fabio Rabelo; Wallerman, Ola; Paivandy, Aida; Calounova, Gabriela; Gustafson, Ann Marie; Sabari, Benjamin R.; Zabucchi, Giuliano; Allis, C. David; Pejler, Gunnar

doi:10.1016/j.jaci.2016.11.044

Cited by 36 publications

(51 citation statements)

References 29 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further address the mechanism behind the impact of Mcpt6 on tumor growth, we hypothesized that Mcpt6 might affect gene expression patterns in the tumors. This was prompted by our previous observations that Mcpt6 can have marked effects on gene expression in MCs (Melo et al, ). To evaluate this possibility, we prepared RNA from multiple tumors of WT and Mcpt6 −/− mice, pooled these, and subjected the samples to gene array analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The aim of this study was to further dissect the impact of the MC proteases on melanoma progression. We thereby focused on tryptase, based on our previous observation that tryptase in certain settings can have an anti‐proliferative action (Melo et al, ). For this purpose, we evaluated mice lacking tryptase Mcpt6 in a subcutaneous model of melanoma.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Grujić

Hellman

Gustafson

et al. 2020

Pigment Cell Melanoma Res

Self Cite

View full text Add to dashboard Cite

Tryptase‐positive mast cells populate melanomas, but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase‐deficient (Mcpt6−/−) versus wild‐type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild‐type and Mcpt6−/− mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase‐positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2, and Gbp10, while the expression of 5p‐miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6−/− versus wild‐type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Grujić

Hellman

Gustafson

et al. 2020

Pigment Cell Melanoma Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus far, diverse families of proteases have been implied in histone H3 clipping, including cathepsin L‐type cysteine proteases , tryptase , glutamate dehydrogenase , Jumonji C domain (JmjC)‐containing proteins, JMJD5 and JMJD7 , and an unidentified yeast enzyme that has intrinsic aminopeptidase and endopeptidase activity . Interestingly, Duncan et al reported that covalent histone modifications modulate cathepsin L activity.…”

Section: Discussionmentioning

confidence: 99%

“…A second study identified an endopeptidase that cleaves the tail of histone H3 in Saccharomyces cerevisiae and showed that the processed form of histone H3 controls the induction of gene expression by potentially clearing repressive PTMs . Finally, a recent study demonstrated that mast cell lineage is governed by the tryptase‐mediated clipping of histone H3 and H2B tails . Thus, the biological outcome of cleavage of histone H3 differs in different organisms and cell types indicating that the clipped form is not just an intermediate of protein turnover.…”

Section: Introductionmentioning

confidence: 99%

Clipped histone H3 is integrated into nucleosomes of DNA replication genes in the human malaria parasite Plasmodium falciparum

et al. 2019

View full text Add to dashboard Cite

Post‐translational modifications of histone H3 N‐terminal tails are key epigenetic regulators of virulence gene expression and sexual commitment in the human malaria parasite Plasmodium falciparum . Here, we identify proteolytic clipping of the N‐terminal tail of nucleosome‐associated histone H3 at amino acid position 21 as a new chromatin modification. A cathepsin C‐like proteolytic clipping activity is observed in nuclear parasite extracts. Notably, an ectopically expressed version of clipped histone H3, PfH3p‐ HA , is targeted to the nucleus and integrates into mononucleosomes. Furthermore, chromatin immunoprecipitation and next‐generation sequencing analysis identified PfH3p‐ HA as being highly enriched in the upstream region of six genes that play a key role in DNA replication and repair: In these genes, PfH3p‐ HA demarcates a specific 1.5 kb chromatin island adjacent to the open reading frame. Our results indicate that, in P. falciparum , the process of histone clipping may precede chromatin integration hinting at preferential targeting of pre‐assembled PfH3p‐containing nucleosomes to specific genomic regions. The discovery of a protease‐directed mode of chromatin organization in P. falciparum opens up new avenues to develop new anti‐malarials.

show abstract

“…Proteolytic removal of the N-terminal tail of histone H3 (histone clipping) has been observed in a number of cell types and physiologic conditions (e.g. Duncan et al, 2008;Santos-Rosa et al, 2009;Duarte et al, 2014;Khalkhali-Ellis et al, 2014;Kim et al, 2016;Melo et al, 2017;Shen et al, 2017). However, it is not known whether this mechanism is involved in neural stem cell differentiation.…”

Section: Cstb Regulates Histone H3 Tail Clipping During Neural Stem Cmentioning

confidence: 99%

Ectopic histone clipping in the mouse model of progressive myoclonus epilepsy

Daura

Tegelberg

Yoshihara

et al. 2020

Preprint

View full text Add to dashboard Cite

We establish cystatin B (CSTB) as a regulator of histone H3 tail clipping in murine neural progenitor cells (NPCs) and provide evidence suggesting that epigenetic dysregulation contributes to the early pathogenesis in brain disorders associated with deficient CSTB function. We show that NPCs undergo regulated cleavage of the N-terminal tail of histone H3 at threonine 22 (H3T22) transiently upon induction of differentiation. CSTB-deficient NPCs present premature activation of H3T22 clipping during self-renewal mediated by increased activity of cathepsins L and B. During differentiation, the proportion of immature committed neurons undergoing H3T22 clipping is significantly higher in CSTB-deficient than in wild-type NPCs, with no observable decline within 12 days post-differentiation. CSTB-deficient NPCs exhibit significant transcriptional changes highlighting altered expression of nuclear-encoded mitochondrial genes. These changes are associated with significantly impaired respiratory capacity of differentiating NPCs devoid of CSTB. Our data expand the mechanistic understanding of diseases associated with CSTB deficiency.

show abstract

Tryptase-catalyzed core histone truncation: A novel epigenetic regulatory mechanism in mast cells

Abstract: These findings introduce tryptase-catalyzed histone clipping as a novel epigenetic regulatory mechanism, which in the mast cell context may be crucial for maintaining cellular identity.

Cited by 36 publications

References 29 publications

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Clipped histone H3 is integrated into nucleosomes of DNA replication genes in the human malaria parasite Plasmodium falciparum

Ectopic histone clipping in the mouse model of progressive myoclonus epilepsy

Contact Info

Product

Resources

About