Um novo princípio para mudanças epigenéticas

terça-feira, janeiro 24, 2017

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

Fabio R. Melo, PhD, Ola Wallerman, PhD∗, Aida Paivandy, MSc∗, Gabriela Calounova, PhD, Ann-Marie Gustafson, Ms, Benjamin R. Sabari, PhD, Giuliano Zabucchi, PhD, C David Allis, PhD, Gunnar Pejler, PhD.

∗Equal contribution

Article Info

Publication History

Published online: January 17, 2017 Accepted: November 29, 2016 Received in revised form: October 28, 2016

Received: May 6, 2016

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Abstract Background

Mast cells are key effector cells in allergic reactions. When activated to degranulate, they release a plethora of bioactive compounds from their secretory granules, including mast cell-restricted proteases such as tryptase. In a previous study we showed that tryptase, in addition to its intragranular location, can be found within the nuclei of mast cells where it truncates core histones at their N-terminal ends.


Considering that the N-terminal portions of the core histones constitute sites for posttranslational modifications of major epigenetic impact, we here evaluated whether histone truncation by tryptase could have an impact on epigenetic events in mast cells.


Mast cells were cultured from wild type and tryptase null mice, followed by an assessment of their profile of epigenetic histone modifications and their phenotypic characteristics.


We show that tryptase truncates nucleosomal histone 3 (H3) and H2B and that its absence results in accumulation of the epigenetic mark, lysine 5-acetylated H2B (H2BK5ac). Intriguingly, the accumulation of H2BK5ac was cell age-dependent and was associated with a profound upregulation of markers of non-mast cell lineages, loss of proliferative control, chromatin remodeling as well as extensive morphological alterations.


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.

Keywordsmast cells, epigenetics, core histones, tryptase, histone acetylation, secretory granules, serglycin proteoglycan

This work was supported by grants from: The Swedish Research Council, The Swedish Cancer Foundation, The Swedish Heart and Lung Foundation, Formas, The Torsten Söderberg Foundation, NIH R01-GM40922 and The Rockefeller University.

FREE PDF GRATIS: The Journal of Allergy and Clinical Immunology (in press) 15 MBs 

© 2017 Published by Elsevier Inc.