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

Beatriz Aranda-Orgilles, Ricardo Saldaña-Meyer, Eric Wang, Eirini Trompouki, Anne Fassl, Stephanie Lau, Jasper Mullenders, Pedro P. Rocha, Ramya Raviram, María Guillamot, María Sánchez-Díaz, Kun Wang, Clarisse Kayembe, Nan Zhang, Leonela Amoasii, Avik Choudhuri, Jane A. Skok, Markus Schober, Danny Reinberg, Piotr Sicinski, Heinrich Schrewe, Aristotelis Tsirigos, Leonard I. Zon, Iannis Aifantis.

Beatriz Aranda-Orgilles, Ph.D.Stem cells rely on the finely coordinated activity of cell-specific transcription factors to self-renew and differentiate (De Los Angeles et al., 2015, Spitz and Furlong, 2012). Key transcription factors, such as GATA2, RUNX1, GFI1, or TAL1, are required to preserve hematopoietic stem cell (HSC) function (Orkin and Zon, 2008, Wilson et al., 2010). HSC function requires a tightly regulated network of transcription factors to guarantee homeostasis and prevent transformation (Lara-Astiaso et al., 2014, Rossi et al., 2012). Transcription factors use coactivators to communicate with the general transcription machinery and ensure that biological inputs received from signaling cascades are translated into specific gene expression programs (Spiegelman and Heinrich, 2004, Weake and Workman, 2010). The Mediator complex is a pivotal coactivator of transcription factor activity that acts as a molecular bridge between transcription factors at enhancers and RNA polymerase II at promoters (Allen and Taatjes, 2015). Mediator is a large macromolecular complex arranged in four modules, the head, the middle, the tail, and the kinase module, the latter being comprised by MED12, MED13, CDK8, and CYCLIN C (Tsai et al., 2014).

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