Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts.
Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts.
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DOI：
10.1038/cddis.2013.146
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发表时间：
2013-05-02
影响因子：
9
通讯作者：
Peters-Golden, M.
中科院分区：
文献类型：
--
作者：
Huang, S. K.;Scruggs, A. M.;Donaghy, J.;Horowitz, J. C.;Zaslona, Z.;Przybranowski, S.;White, E. S.;Peters-Golden, M.
Although the recruitment of fibroblasts to areas of injury is critical for wound healing, their subsequent apoptosis is necessary in order to prevent excessive scarring. Fibroproliferative diseases, such as pulmonary fibrosis, are often characterized by fibroblast resistance to apoptosis, but the mechanism(s) for this resistance remains elusive. Here, we employed a murine model of pulmonary fibrosis and cells from patients with idiopathic pulmonary fibrosis (IPF) to explore epigenetic mechanisms that may be responsible for the decreased expression of Fas, a cell surface death receptor whose expression has been observed to be decreased in pulmonary fibrosis. Murine pulmonary fibrosis was elicited by intratracheal injection of bleomycin. Fibroblasts cultured from bleomycin-treated mice exhibited decreased Fas expression and resistance to Fas-mediated apoptosis compared with cells from saline-treated control mice. Although there were no differences in DNA methylation, the Fas promoter in fibroblasts from bleomycin-treated mice exhibited decreased histone acetylation and increased histone 3 lysine 9 trimethylation (H3K9Me3). This was associated with increased histone deacetylase (HDAC)-2 and HDAC4 expression. Treatment with HDAC inhibitors increased Fas expression and restored susceptibility to Fas-mediated apoptosis. Fibroblasts from patients with IPF likewise exhibited decreased histone acetylation and increased H3K9Me3 at the Fas promoter and increased their expression of Fas in the presence of an HDAC inhibitor. These findings demonstrate the critical role of histone modifications in the development of fibroblast resistance to apoptosis in both a murine model and in patients with pulmonary fibrosis and suggest novel approaches to therapy for progressive fibroproliferative disorders.
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DOI：
10.1016/j.biocel.2011.10.011
发表时间：
2012-01
影响因子：
4
作者：
Horowitz, Jeffrey C.;Ajayi, Iyabode O.;Kulasekaran, Priya;Rogers, David S.;White, Joshua B.;Townsend, Sarah K.;White, Eric S.;Nho, Richard S.;Higgins, Peter D. R.;Huang, Steven K.;Sisson, Thomas H.
通讯作者：
Sisson, Thomas H.
影响因子：
5.7
作者：
Gillenwater, Ann M.;Zhong, Meiling;Lotan, Reuben
通讯作者：
Lotan, Reuben
影响因子：
4.3
作者：
Garcia-Sancho Figueroa, Ma. Cecilia;Carrillo, Guillermo;Selman, Moises
通讯作者：
Selman, Moises
影响因子：
5.3
作者：
Anathy, Vikas;Roberson, Elle;Janssen-Heininger, Yvonne M. W.
通讯作者：
Janssen-Heininger, Yvonne M. W.
影响因子：
56.9
作者：
GRIFFITH, TS;BRUNNER, T;FERGUSON, TA
通讯作者：
FERGUSON, TA