MED12 in hematopoietic stem cells-cell specific function despite ubiquitous expression.

All cells contain several multi-component molecular machines for executing steps in the fundamental cellular processes of transcription and translation. Paradoxically, despite their ubiquitous expression, individual components of these protein conglomerates are responsible for extraordinarily cell-specific functions. One of these fundamental molecular complexes is Mediator. Mediator is expressed and required in cells where genes are actively being expressed. Its major role is to act as a molecular bridge anchoring two regions of otherwise unconnected DNA (promoter and enhancer), bringing together the constellation of promoter and enhancer associated transcription factors required for expression of genes transcribed by RNA polymerase II. It also plays associated roles in architecting chromatin organisation, transcription preand re-initiation, elongation and pausing [reviewed in Allen and Taatjes, 2015 (1)]. MED12 is one component of the four-part kinase module of Mediator a long with MED13, cycl independent kinase 8 (CDK8) and cyclin C (CCNC), which regulates the function of Mediator. Mutations in MED12 were originally associated with intellectual disabi l i ty syndromes including Lujan (2) , OpitzKaveggia (3), and Ohdo syndromes (4). Since then, strong association of acquired somatic mutations in MED12 with uterine leiomyoma has surfaced (5). An essential, specific hematopoietic role for Med12 in myelopoiesis and T cell development was evident from analysis of the syrah zebrafish mutant that resulted from a forward genetic screen to identify as yet unrecognised factors important for myeloid development (6). Somatic mutations in MED12 have since been associated with or identified as driver mutations in Tand NK-cell posttransplant lymphoproliferative disorders (7) and pediatric T-cell acute lymphoblastic leukemia (8), and are a poor prognosis marker in chronic lymphocytic leukemia (9). How ubiquitously expressed components of a universally required macromolecular machine can generate cellspecific functional outcomes is an intriguing mechanistic question that has been elegantly explored by ArandaOrgilles et al. in their recent paper published in Cell Stem Cell using MED12 and its role in hematopoiesis as an exemplar (10). Two different conditional knockout approaches allowing specific deletion of MED12 in the hematopoietic system of both neonates and adults enabled a requirement for MED12 in maintaining hematopoietic stem cell (HSC) number and function to be demonstrated. HSCs and progenitors were largely absent in MED12 deleted animals and failed to engraft. Even after permitting equivalent engraftment by transplanting prior to inducing Cre recombinase expression, transplanted HSCs with subsequent deletion of MED12 failed to reconstitute blood lineages in competitive bone marrow transplant assays, pointing to a failure in de novo Editorial