The histone demethylase PHF8 facilitates alternative splicing of the histocompatibility antigen HLA-G

FEBS Letters

article

Matthias S. Leisegang¹  Lunda Gu¹  Jens Preussner²  Stefan Günther²  Juliane Hitzel¹  Corina Ratiu¹  Andreas Weigert⁵  Wei Chen²  Eva C. Schwarz⁸  Mario Looso²  Christian Fork¹  Ralf P. Brandes¹ 

[1] Institute for Cardiovascular Physiology, Medical Faculty, Goethe University;German Center for Cardiovascular Research (DZHK);Max-Planck-Institute for Heart and Lung Research;Department of Functional Sciences – Pathophysiology, “Victor Babes” University of Medicine and Pharmacy Timisoara;Faculty of Medicine, Institute of Biochemistry I, Goethe University;Laboratory for Novel Sequencing Technology, Max-Delbrück-Center for Molecular Medicine;Department of Biology, Southern University of Science and Technology;Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University

关键词: endothelium;    epigenetics;    HLA-G;    PHF8;    splicing;   

DOI  :  10.1002/1873-3468.13337

来源: John Wiley & Sons Ltd.

【 摘 要 】

Histone3-lysine9 (H3K9) residues not only control gene expression, but also contribute to RNA splicing. Here, the H3K9 histone demethylase PHF8 was investigated in endothelial cells for its involvement in alternative splicing. An angiogenic sprouting assay shows the importance of PHF8 for endothelial cells. Immunoprecipitation reveals that PHF8 interacts with U1 spliceosomal proteins, such as SRPK1 and snRNP70. We identify the histocompatibility antigen HLA-G as a target of PHF8. The inclusion of HLA-G intron 4, with concomitant RNA Polymerase II accumulation at this intron is controlled by PHF8 and H3K9. Soluble HLA-G is generated after PHF8 knockdown, which leads to reduced T-cell proliferation. Collectively, PHF8 knockdown generates the immunosuppressive alternative splice product soluble HLA-G, which is secreted by endothelial cells to elicit a potential inhibitory effect on inflammation.

【 授权许可】

Unknown