title: SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation.
abstract: Reversible methylation of lysine residues has emerged as a central mechanism for epigenetic regulation and is a component of the "histone code," which engenders histones with gene regulatory information. KDM4A is a histone demethylase that targets tri- and dimethylation marks on histone H3 lysines 9 and 36. While the abundance of KDM4A oscillates in the cell cycle, little is known how this enzyme is regulated to achieve targeted effects on specific histone residues in chromatin. Here, we report that a previously unstudied SCF(FBXO22) ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction (FIST) domain. Modulation of FBXO22 levels by RNA interference or overexpression leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2. Taken together, these results demonstrate that SCF(FBXO22) regulates changes in histone H3 marks and cognate transcriptional control pathways by controlling KDM4A levels, and they suggest a potential role for FBXO22 in development, differentiation, and disease through spatial and temporal control of KDM4A activity.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Meng-Kwang Marcus
authors.initials: MK
authors.lastname: Tan
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Lim
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin; D003517:Cyclopentanes / Q000494:pharmacology; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000378:metabolism*; D013058:Mass Spectrometry; D008745:Methylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011719:Pyrazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001897:Boronic Acids; D000069286:Bortezomib; D018797:Cell Cycle Proteins; D002843:Chromatin; D003517:Cyclopentanes; D044783:F-Box Proteins; D056466:Histone Demethylases; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; C065501:ASCL2 protein, human; C561886:FBXO22 protein, human; C494424:KDM4A protein, human; C539933:pevonedistat