RESUMEN
Cell cycle dynamics has emerged as a key regulator of stem cell fate decisions. In particular, differentiation decisions are associated with the G1 phase, and recent evidence suggests that self-renewal is actively regulated outside of G1. The mechanisms underlying these phenomena are largely unknown, but direct control of gene regulatory programs by the cell cycle machinery is heavily implicated. A recent study sheds important mechanistic insight by demonstrating that in human embryonic stem cells (hESCs) the Cyclin-dependent kinase CDK2 controls a wide-spread epigenetic program that drives transcription at differentiation-related gene promoters specifically in G1. Here, we discuss this finding and explore whether similar mechanisms are likely to function in multipotent stem cells. The implications of this discovery toward our understanding of stem cell-related disease are discussed, and we postulate novel mechanisms that position the cell cycle as a regulator of cell fate gene networks at epigenetic, transcriptional and post-transcriptional levels.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/genética , Células Madre Embrionarias/metabolismo , Epigénesis Genética , Fase G1/genética , Células-Madre Neurales/metabolismo , Células Madre Pluripotentes/metabolismo , Diferenciación Celular , Quinasa 2 Dependiente de la Ciclina/metabolismo , Células Madre Embrionarias/citología , Redes Reguladoras de Genes , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Células-Madre Neurales/citología , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Células Madre Pluripotentes/citología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Transcripción GenéticaRESUMEN
Polycomb repressive complex 2 (PRC2) accessory proteins play substoichiometric, tissue-specific roles to recruit PRC2 to specific genomic loci or increase enzymatic activity, while PRC2 core proteins are required for complex stability and global levels of trimethylation of histone 3 at lysine 27 (H3K27me3). Here, we demonstrate a role for the classical PRC2 accessory protein Mtf2/Pcl2 in the hematopoietic system that is more akin to that of a core PRC2 protein. Mtf2-/- erythroid progenitors demonstrate markedly decreased core PRC2 protein levels and a global loss of H3K27me3 at promoter-proximal regions. The resulting de-repression of transcriptional and signaling networks blocks definitive erythroid development, culminating in Mtf2-/- embryos dying by e15.5 due to severe anemia. Gene regulatory network (GRN) analysis demonstrated Mtf2 directly regulates Wnt signaling in erythroblasts, leading to activated canonical Wnt signaling in Mtf2-deficient erythroblasts, while chemical inhibition of canonical Wnt signaling rescued Mtf2-deficient erythroblast differentiation in vitro. Using a combination of in vitro, in vivo and systems analyses, we demonstrate that Mtf2 is a critical epigenetic regulator of Wnt signaling during erythropoiesis and recast the role of polycomb accessory proteins in a tissue-specific context.