Description:
<jats:p>Histone3‐lysine9 (H3K9) residues not only control gene expression, but also contribute to <jats:styled-content style="fixed-case">RNA</jats:styled-content> splicing. Here, the H3K9 histone demethylase <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 was investigated in endothelial cells for its involvement in alternative splicing. An angiogenic sprouting assay shows the importance of <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 for endothelial cells. Immunoprecipitation reveals that <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 interacts with U1 spliceosomal proteins, such as <jats:styled-content style="fixed-case">SRPK</jats:styled-content>1 and sn<jats:styled-content style="fixed-case">RNP</jats:styled-content>70. We identify the histocompatibility antigen <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐G as a target of <jats:styled-content style="fixed-case">PHF</jats:styled-content>8. The inclusion of <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐G intron 4, with concomitant <jats:styled-content style="fixed-case">RNA</jats:styled-content> Polymerase <jats:styled-content style="fixed-case">II</jats:styled-content> accumulation at this intron is controlled by <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 and H3K9. Soluble <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐G is generated after <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 knockdown, which leads to reduced T‐cell proliferation. Collectively, <jats:styled-content style="fixed-case">PHF</jats:styled-content>8 knockdown generates the immunosuppressive alternative splice product soluble <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐G, which is secreted by endothelial cells to elicit a potential inhibitory effect on inflammation.</jats:p>