IRF2 is a master regulator of human keratinocyte stem cell fate
IRF2 is a master regulator of human keratinocyte stem cell fate
复制标题
DOI：
10.1038/s41467-019-12559-x
复制
发表时间：
2019-10-14
影响因子：
16.6
通讯作者：
Kirkland, Susan
中科院分区：
文献类型：
--
作者：
Mercado, Nicolas;Schutzius, Gabi;Kirkland, Susan
常驻成体上皮干细胞通过平衡自我更新和分化来维持组织稳态。人表皮角质形成细胞的干细胞潜能在体外被保留，但随着时间的推移而丧失，这表明了外在和内在的调节。转录因子控制的调控回路控制细胞的身份，足以诱导多能性和转分化细胞。我们调查是否转录电路也管理一个给定的细胞类型内的表型变化，通过比较人的原代角质形成细胞固有的高与低干细胞的潜力。使用整合的染色质和转录分析，我们牵连IRF 2作为拮抗干，并表明它结合和调节活性顺式调节元件在干扰素反应和抗原呈递基因。具有低干细胞潜能的角质形成细胞中IRF 2的CRISPR-KD增加自我更新、迁移和表皮形成。这些数据表明，转录因子调节电路，除了保持细胞的身份，控制可塑性的细胞类型，并提供潜在的细胞功能的治疗调制。
Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factorcontrolled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells. We investigate whether transcriptional circuitry also governs phenotypic changes within a given cell type by comparing human primary keratinocytes with intrinsically high versus low stem cell potential. Using integrated chromatin and transcriptional profiling, we implicate IRF2 as antagonistic to stemness and show that it binds and regulates active cis-regulatory elements at interferon response and antigen presentation genes. CRISPR-KD of IRF2 in keratinocytes with low stem cell potential increases self-renewal, migration and epidermis formation. These data demonstrate that transcription factor regulatory circuitries, in addition to maintaining cell identity, control plasticity within cell types and offer potential for therapeutic modulation of cell function.