Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1
Open Access
- 26 April 2013
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 41 (12), 6005-6017
- https://doi.org/10.1093/nar/gkt311
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.Keywords
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