There will be blood: hematopoiesis control by mediator subunit MED12

Thomas G. Boyer


Hematopoiesis is sustained by the presence of hematopoietic stem cells (HSCs) that balance self-renewal and differentiation through controlled expression of enhancer-dependent transcriptional programs enforced by lineage-specific master transcription factors. The regulatory potential of these cardinal transcription factors is often realized with the assistance of Mediator, a conserved multiprotein interface between distal, enhancer-bound regulators and the RNA polymerase II machinery assembled on core promoters. Within Mediator, CDK8 and its partner Cyclin C (CycC) combine with MED12 and MED13 to form a 4-subunit kinase module that variably associates with a 26-subunit Mediator core (1). MED12, which anchors and activates CycC-CDK8 in Mediator, has previously been implicated in hematopoiesis through forward genetic and mutational screening in zebrafish embryos and human cancers, respectively, revealing links to both myelopoiesis and leukemia (2,3). However, the molecular basis for MED12 in these biological and pathological processes is unclear. Against this backdrop, the Aifantis laboratory recently undertook to more rigorously investigate the role of MED12 in the hematopoietic system (4).