Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1

Nucleic Acids Res. 2013 Jul;41(12):6005-17. doi: 10.1093/nar/gkt311. Epub 2013 Apr 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cells, Cultured
  • DNA Helicases / metabolism
  • DNA Helicases / physiology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism*
  • Endothelial Cells / metabolism*
  • Endothelin-1 / genetics*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Epigenesis, Genetic*
  • Histones / metabolism
  • Humans
  • Mice
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • Oncogene Proteins, Fusion / biosynthesis
  • Oncogene Proteins, Fusion / metabolism*
  • Promoter Regions, Genetic
  • Serum Response Factor / metabolism
  • Trans-Activators
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Transcriptional Activation*


  • DNA-Binding Proteins
  • Endothelin-1
  • Histones
  • MRTFA protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • SMARCA2 protein, human
  • Serum Response Factor
  • Trans-Activators
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases