4.8 Article

Tryptase Regulates the Epigenetic Modification of Core Histones in Mast Cell Leukemia Cells

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FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.804408

关键词

tryptase; histones; mast cells; epigenetics; apoptosis

资金

  1. Swedish Research Council
  2. Swedish Heart and Lung Foundation
  3. Swedish Cancer Foundation
  4. Knut & Alice Wallenberg Foundation
  5. Saudi Arabian Ministry of Education

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This study reveals the significant role of tryptase in core histone processing and epigenetic modification in human mast cell leukemia cells, where inhibition of tryptase can reverse the effects of cell death on these modifications. The presence of tryptase in the nucleus suggests its involvement in regulating nuclear events and controlling cell proliferation.
Mast cells are immune cells that store large amounts of mast cell-restricted proteases in their secretory granules, including tryptase, chymase and carboxypeptidase A3. In mouse mast cells, it has been shown that tryptase, in addition to its canonical location in secretory granules, can be found in the nuclear compartment where it can impact on core histones. Here we asked whether tryptase can execute core histone processing in human mast cell leukemia cells, and whether tryptase thereby can affect the epigenetic modification of core histones. Our findings reveal that triggering of cell death in HMC-1 mast cell leukemia cells is associated with extensive cleavage of core histone 3 (H3) and more restricted cleavage of H2B. Tryptase inhibition caused a complete blockade of such processing. Our data also show that HMC-1 cell death was associated with a major reduction of several epigenetic histone marks, including H3 lysine-4-mono-methylation (H3K4me1), H3K9me2, H3 serine-10-phosphorylation (H3S10p) and H2B lysine-16-acetylation (H2BK16ac), and that tryptase inhibition reverses the effect of cell death on these epigenetic marks. Further, we show that tryptase is present in the nucleus of both viable and dying mast cell leukemia cells. In line with a role for tryptase in regulating nuclear events, tryptase inhibition caused increased proliferation of the mast cell leukemia cells. Altogether, the present study emphasizes a novel principle for how epigenetic modification of core histones is regulated, and provides novel insight into the biological function of human mast cell tryptase.

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