title: The Histone Demethylase PHF8 Is Essential for Endothelial Cell Migration.
abstract: Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function.
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.
authors.forename: Lunda
authors.initials: L
authors.lastname: Gu
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hitzel
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Moll
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kruse
authors.affiliation: Institute of Vascular Signalling, Centre for Molecular Medicine, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Randa Abdel
authors.initials: RA
authors.lastname: Malik
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Preussner
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Looso
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Leisegang
authors.affiliation: Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Institute for Cardiovascular Physiology, Medical Faculty, Goethe-University Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fork
mesh_terms: D017209:Apoptosis; D002384:Catalysis; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D019175:DNA Methylation; D050704:E2F4 Transcription Factor / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008833:Microcirculation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D056466:Histone Demethylases; C511934:PHF8 protein, human