title: LSD1 regulates pluripotency of embryonic stem/carcinoma cells through histone deacetylase 1-mediated deacetylation of histone H4 at lysine 16.
abstract: LSD1 is essential for the maintenance of pluripotency of embryonic stem (ES) or embryonic carcinoma/teratocarcinoma (EC) cells. We have previously developed novel LSD1 inhibitors that selectively inhibit ES/EC cells. However, the critical targets of LSD1 remain unclear. Here, we found that LSD1 interacts with histone deacetylase 1 (HDAC1) to regulate the proliferation of ES/EC cells through acetylation of histone H4 at lysine 16 (H4K16), which we show is a critical substrate of HDAC1. The LSD1 demethylase and HDAC1 deacetylase activities were both inactivated if one of them in the complex was chemically inhibited in ES/EC cells or in reconstituted protein complexes. Loss of HDAC1 phenocopied the selective growth-inhibitory effects and increased the levels of H3K4 methylation and H4K16 acetylation of LSD1 inactivation on ES/EC cells. Reduction of acetylated H4K16 by ablation of the acetyltransferase males absent on the first (MOF) is sufficient to rescue the growth inhibition induced by LSD1 inactivation. While LSD1 or HDAC1 inactivation caused the downregulation of Sox2 and Oct4 and induction of differentiation genes, such as FOXA2 or BMP2, depletion of MOF restored the levels of Sox2, Oct4, and FoxA2 in LSD1-deficient cells. Our studies reveal a novel mechanism by which LSD1 acts through the HDAC1- and MOF-mediated regulation of H4K16 acetylation to maintain the pluripotency of ES/EC cells.
authors.affiliation: Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Lan
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Linyu
authors.initials: L
authors.lastname: Zhu
authors.forename: Fangfang
authors.initials: F
authors.lastname: Chen
authors.forename: Zhengshuang
authors.initials: Z
authors.lastname: Xu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D054278:Embryonal Carcinoma Stem Cells / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology; D044127:Epigenesis, Genetic; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D045325:HCT116 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000502:physiology*; D056466:Histone Demethylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D006657:Histones; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C121019:RCOR1 protein, human; D012097:Repressor Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D008239:Lysine