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Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice

2015; Nature Portfolio; Volume: 521; Issue: 7552 Linguagem: Inglês

10.1038/nature14289

1476-4687

Rene C. Adam, Hanseul Yang, Shira Rockowitz, Samantha B. Larsen, Maria Nikolova, Daniel Oristian, Lisa Polak, Meelis Kadaja, Amma Asare, Deyou Zheng, Elaine Fuchs,

RNA Research and Splicing

An analysis of mouse skin reveals that super-enhancers are critical to identity, lineage commitment and plasticity of adult stem cells; dynamic super-enhancer remodelling in new niches is dependent on the levels of pioneer transcription factor SOX9, which is identified as a key regulator of super-enhancer chromatin for hair follicle stem cells. Adult stem cells are able to differentiate along a lineage and also to transiently exit their native niche while retaining their plasticity. Here, Elaine Fuchs and colleagues analyse super-enhancers and chromatin dynamics in mouse hair follicle stem cells in vivo, both during lineage progression and when the stem cells are outside their niche and exposed to a new environment. The pioneer factor SOX9 — a type of transcription factor that binds directly to condensed chromatin — is identified as a crucial regulator of the hair follicle stem cells' super-enhancers in promoting and maintaining cell fate. Adult stem cells occur in niches that balance self-renewal with lineage selection and progression during tissue homeostasis. Following injury, culture or transplantation, stem cells outside their niche often display fate flexibility1,2,3,4. Here we show that super-enhancers5 underlie the identity, lineage commitment and plasticity of adult stem cells in vivo. Using hair follicle as a model, we map the global chromatin domains of hair follicle stem cells and their committed progenitors in their native microenvironments. We show that super-enhancers and their dense clusters (‘epicentres’) of transcription factor binding sites undergo remodelling upon lineage progression. New fate is acquired by decommissioning old and establishing new super-enhancers and/or epicentres, an auto-regulatory process that abates one master regulator subset while enhancing another. We further show that when outside their niche, either in vitro or in wound-repair, hair follicle stem cells dynamically remodel super-enhancers in response to changes in their microenvironment. Intriguingly, some key super-enhancers shift epicentres, enabling their genes to remain active and maintain a transitional state in an ever-changing transcriptional landscape. Finally, we identify SOX9 as a crucial chromatin rheostat of hair follicle stem cell super-enhancers, and provide functional evidence that super-enhancers are dynamic, dense transcription-factor-binding platforms which are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states and differentiation.