title: Thyroid hormone increases bulk histones expression by enhancing translational efficiency.
abstract: The expression of canonical histones is normally coupled to DNA synthesis during the S phase of the cell cycle. Replication-dependent histone mRNAs do not contain a poly(A) tail at their 3' terminus, but instead possess a stem-loop motif, the binding site for the stem-loop binding protein (SLBP), which regulates mRNA processing, stability, and relocation to polysomes. Here we show that the thyroid hormone can increase the levels of canonical histones independent of DNA replication. Incubation of mouse embryonic fibroblasts with T3 increases the total levels of histones, and expression of the thyroid hormone receptor β induces a further increase. This is not restricted to mouse embryonic fibroblasts, because T3 also raises histone expression in other cell lines. T3 does not increase histone mRNA or SLBP levels, suggesting that T3 regulates histone expression by a posttranscriptional mechanism. Indeed, T3 enhanced translational efficiency, inducing relocation of histone mRNA to heavy polysomes. Increased translation was associated with augmented transcription of the eukaryotic translation initiation factor 4 γ2 (EIF4G2). T3 induced EIF4G2 protein and mRNA levels and the thyroid hormone receptor bound to the promoter region of the Eif4g2 gene. Induction of EIF4G2 was essential for T3-dependent histone induction, because depletion of this factor abolished histone increase. These results point out the importance of the thyroid hormones on the posttranscriptional regulation of histone biosynthesis in a cell cycle-independent manner and also suggest the potential regulation of eukaryotic translation by the modulation of the initiation factor EIF4G2, which also operates in the translation of canonical mRNAs.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambrano
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Carpizo
authors.forename: Raquel
authors.initials: R
authors.lastname: Villamuera
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D004261:DNA Replication / Q000235:genetics; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006657:Histones / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis / Q000502:physiology*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000096:biosynthesis* / Q000235:genetics; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: C104828:Eif4g2 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013974:Thyroxine