Mediator 1 ablation induces enamel-to-hair lineage conversion in mice through enhancer dynamics.
Mediator 1 ablation induces enamel-to-hair lineage conversion in mice through enhancer dynamics.
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DOI：
10.1038/s42003-023-05105-5
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发表时间：
2023-07-21
影响因子：
5.9
通讯作者：
Oda, Yuko
中科院分区：
文献类型：
--
作者：
Thaler, Roman;Yoshizaki, Keigo;Nguyen, Thai;Fukumoto, Satoshi;Den Besten, Pamela;Bikle, Daniel D.;Oda, Yuko
出生后的细胞命运被假定主要由局部组织微环境决定。在这里，我们发现，中介1（Med 1）依赖的表观遗传机制决定组织特异性谱系承诺和牙齿上皮细胞的进展。Med 1是将增强子活性与基因转录联系起来的介体复合物的关键成分，Med 1的缺失引起组织外在谱系转变，导致切牙中的毛发生成。Med 1缺乏通过原始细胞聚集引起不寻常的毛发生长。从机制上讲，我们发现MED 1在牙齿干细胞及其后代中建立了控制釉质谱系转录因子的超级增强子。然而，Med 1缺陷重塑增强子景观，并导致从牙齿转录程序向体内门牙上的毛发和表皮以及体外牙齿上皮干细胞的切换。Med 1的丢失也引起增强子数量和大小的增加。有趣的是，对照牙上皮细胞已经表现出毛发和表皮关键转录因子的增强子;这些在Med 1丢失后转化为超级增强子，表明这些表观遗传机制导致向表皮和毛发谱系的转变。因此，我们提出了Med 1在保护谱系特异性增强子中的作用，强调了增强子可及性在谱系重编程中的核心作用，并提供了对外胚层再生的见解。RNA-seq和ChIP-seq分析表明，介体1消融诱导的牙釉质-毛发谱系转变是增强子动力学变化的结果。
Postnatal cell fate is postulated to be primarily determined by the local tissue microenvironment. Here, we find that Mediator 1 (Med1) dependent epigenetic mechanisms dictate tissue-specific lineage commitment and progression of dental epithelia. Deletion 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 incisors. Med1 deficiency gives rise to unusual hair growth via primitive cellular aggregates. Mechanistically, we find that MED1 establishes super-enhancers that control enamel lineage transcription factors in dental stem cells and their progenies. However, Med1 deficiency reshapes the enhancer landscape and causes a switch from the dental transcriptional program towards hair and epidermis on incisors in vivo, and in dental epithelial stem cells in vitro. Med1 loss also provokes an increase in the number and size of enhancers. Interestingly, control dental epithelia already exhibit enhancers for hair and epidermal key transcription factors; these transform into super-enhancers upon Med1 loss suggesting that these epigenetic mechanisms cause the shift towards epidermal and hair lineages. Thus, we propose a role for Med1 in safeguarding lineage specific enhancers, highlight the central role of enhancer accessibility in lineage reprogramming and provide insights into ectodermal regeneration. RNA-seq and ChIP-seq analysis shows that enamel-hair lineage transition induced by Mediator 1 ablation results from changes in enhancer dynamics.
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