title: Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation.
abstract: The ligand-bound thyroid hormone receptor (TR) is known to repress via a negative TRE (nTRE) the expression of E2F1, a key transcription factor that controls the G1/S phase transition. Alien has been identified as a novel interacting factor of E2F1 and acts as a corepressor of E2F1. The detailed molecular mechanism by which Alien inhibits E2F1 gene expression remains unclear. Here, we report that the histone H3 lysine 9 (H3K9) methyltransferase (HMT) ESET is an integral component of the corepressor Alien complex and the Alien/ESET complex is recruited to both sites, the E2F1 and the nTRE site of the E2F1 gene while the recruitment to the negative thyroid hormone response element (nTRE) is induced by the ligand-bound TRβ1 within the E2F1 gene promoter. We show that, overexpression of ESET promotes, whereas knockdown of ESET releases, the inhibition of TRβ1-regulated gene transcription upon T3 stimulation; and H3K9 methylation is required for TRβ1-repressed transcription. Furthermore, depletion of ESET impairs thyroid hormone-repressed proliferation as well as the G1/S transition of the cell cycle. Taken together, our data indicate that ESET is involved in TRβ1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation.
authors.affiliation: Department of Immunology, Tianjin Medical University, 300070 Tianjin, China. hongwei@tijmu.edu.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.forename: Jinru
authors.initials: J
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chen
authors.forename: Wenyan
authors.initials: W
authors.lastname: Niu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Aria
authors.initials: A
authors.lastname: Baniahmad
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D050687:E2F1 Transcription Factor / Q000235:genetics*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
chemical_list: C118919:Cops2 protein, mouse; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014157:Transcription Factors; D014284:Triiodothyronine; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D000075686:COP9 Signalosome Complex