MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis

Cell Stem Cell. 2016 Dec 1;19(6):784-799. doi: 10.1016/j.stem.2016.08.004. Epub 2016 Aug 25.


Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Bone Marrow / pathology
  • Cell Survival / genetics
  • Chromatin / metabolism
  • Enhancer Elements, Genetic / genetics*
  • Gene Deletion
  • Gene Expression Profiling
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Mediator Complex / metabolism*
  • Mice
  • Protein Binding
  • Transcription Factors / metabolism
  • p300-CBP Transcription Factors / metabolism


  • Chromatin
  • Med12 protein, mouse
  • Mediator Complex
  • Transcription Factors
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor