title: Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice.
abstract: 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.
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Rene C
authors: RC
authors: Adam
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Hanseul
authors: H
authors: Yang
authors: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Shira
authors: S
authors: Rockowitz
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Samantha B
authors: SB
authors: Larsen
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Maria
authors: M
authors: Nikolova
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Daniel S
authors: DS
authors: Oristian
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Lisa
authors: L
authors: Polak
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Meelis
authors: M
authors: Kadaja
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Amma
authors: A
authors: Asare
authors: 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.
authors: Deyou
authors: D
authors: Zheng
authors: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology &Development, The Rockefeller University, New York, New York 10065, USA.
authors: Elaine
authors: E
authors: Fuchs
mesh_terms: D000222:Adaptation, Physiological; D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D018859:Hair Follicle / Q000166:cytology*; D051379:Mice; D009928:Organ Specificity; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D055153:Stem Cell Niche; D013997:Time Factors
chemical_list: D002843:Chromatin; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse