Mediator 1 ablation induces enamel-to-hair lineage conversion through enhancer dynamics

Abstract: Adult stem cell fate has been postulated to be primarily determined by the local tissue microenvironment. Here, we found that Mediator 1 (Med1) dependent epigenetic mechanisms dictate tissue-specific lineage commitment and progression of dental epithelial stem cells. Conditional loss of Med1, a key component of the Mediator complex linking enhancer activities to gene transcription, provokes a tissue extrinsic lineage shift, causing hair generation in the dental environment. Mechanistically, we found that Med1 establishes super-enhancers that control enamel lineage driven transcription factors in control dental stem cells and progenies. However, Med1 deficiency ablates this epigenetic circuit and causes a switch from the dental epithelial transcriptional program towards hair and epidermis on incisors in vivo, and in dental stem cell culture in vitro. Med1 loss also provokes an increase in enhancers and super-enhancers near epidermal and hair genes. Interestingly, control incisors already exhibit enhancers near hair and epidermal key transcription factors; these expand in size and transform into super-enhancers upon Med1 loss indicating that these epigenetic mechanisms cause the transcriptomic and phenotypic shift towards epidermal and hair lineages. Thus, we propose a role for Med1 as safeguard of the tissue-specific epigenome during adult stem cell differentiation, highlight the central role of enhancer accessibility and usage in adult stem cell lineage and provide new insights into ectodermal regeneration.