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FEBS Lett. 2019 Mar;593(5):487-498. doi: 10.1002/1873-3468.13337. Epub 2019 Feb 27.

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

Author information

1
Institute for Cardiovascular Physiology, Medical Faculty, Goethe University, Frankfurt, Germany.
2
German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
3
ECCPS Bioinformatics and Sequencing Facility, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
4
Department of Functional Sciences - Pathophysiology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Romania.
5
Faculty of Medicine, Institute of Biochemistry I, Goethe University, Frankfurt, Germany.
6
Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
7
Department of Biology, Southern University of Science and Technology, Shenzhen, China.
8
Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.

Abstract

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.

KEYWORDS:

HLA-G; PHF8; endothelium; epigenetics; splicing

PMID:
30758047
DOI:
10.1002/1873-3468.13337

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