title: The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts.
abstract: Parathyroid hormone (PTH) is an essential regulator of endochondral bone formation and an important anabolic agent for the reversal of bone loss. PTH mediates its functions in part by regulating binding of the bone-related activating transcription factor 4 (ATF4) to the osteoblast-specific gene, osteocalcin. The basic helix-loop-helix (bHLH) factors Twist1 and Twist2 also regulate osteocalcin transcription in part through the interaction of the C-terminal "box" domain in these factors and Runx2. In this study, we discovered a novel function of PTH: its ability to dramatically decrease Twist1 transcription. Since ATF4 is a major regulator of the PTH response in osteoblasts, we assessed the mutual regulation between these factors and determined that Twist proteins and ATF4 physically interact in a manner that affects ATF4 DNA binding function. We mapped the interaction domain of Twist proteins to the C-terminal "box" domain and of ATF4, to the N-terminus. Furthermore, we demonstrate that Twist1 overexpression in osteoblasts attenuates ATF4 binding to the osteocalcin promoter in response to PTH. This study thus identifies Twist proteins as novel inhibitory binding partners of ATF4 and explores the functional significance of this interaction.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1245, USA. tdanciu@umich.edu
authors.forename: Theodora E
authors.initials: TE
authors.lastname: Danciu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Amy
authors.initials: A
authors.lastname: Koh
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
authors.forename: Renny T
authors.initials: RT
authors.lastname: Franceschi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001846:Bone Development / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; C493709:RUNX2 protein, human; D012097:Repressor Proteins; C103173:TWIST1 protein, human; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1; D015675:Osteocalcin; D051701:Activating Transcription Factor 4