title: Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1.
abstract: Increased synthesis of endothelin-1 (ET-1) by human vascular endothelial cells (HVECs) in response to hypoxia underscores persistent vasoconstriction observed in patients with pulmonary hypertension. The molecular mechanism whereby hypoxia stimulates ET-1 gene transcription is not well understood. Here we report that megakaryocytic leukemia 1 (MKL1) potentiated hypoxia-induced ET-1 transactivation in HVECs. Disruption of MKL1 activity by either a dominant negative mutant or small interfering RNA mediated knockdown dampened ET-1 synthesis. MKL1 was recruited to the proximal ET-1 promoter region (-81/+150) in HVECs challenged with hypoxic stress by the sequence-specific transcription factor serum response factor (SRF). Depletion of SRF blocked MKL1 recruitment and blunted ET-1 transactivation by hypoxia. Chromatin immunoprecipitation analysis of the ET-1 promoter revealed that MKL1 loss-of-function erased histone modifications consistent with transcriptional activation. In addition, MKL1 was indispensable for the occupancy of Brg1 and Brm, key components of the chromatin remodeling complex, on the ET-1 promoter. Brg1 and Brm modulated ET-1 transactivation by impacting histone modifications. In conclusion, our data have delineated a MKL1-centered complex that links epigenetic maneuverings to ET-1 transactivation in HVECs under hypoxic conditions.
authors.affiliation: Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.forename: Dewei
authors.initials: D
authors.lastname: Chen
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: Xian
authors.initials: X
authors.lastname: Cheng
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004265:DNA Helicases / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D019332:Endothelin-1; D006657:Histones; C431575:MRTFA protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C084011:SMARCA2 protein, human; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases