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Nature. 2015 May 21;521(7552):366-70. doi: 10.1038/nature14289. Epub 2015 Mar 18.

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

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Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
1] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.


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 flexibility. Here we show that super-enhancers 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.

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