Departments of Medicine and Endocrinology, United States.
Department of Dermatology, University of California San Francisco, United States; San Francisco VA Health Care system, United States.
J Steroid Biochem Mol Biol. 2023 Sep;232:106352. doi: 10.1016/j.jsbmb.2023.106352. Epub 2023 Jun 16.
The vitamin D receptor with its ligand 1,25 dihydroxy vitamin D (1,25D) regulates epidermal stem cell fate, such that VDR removal from Krt14 expressing keratinocytes delays re-epithelialization of epidermis after wound injury in mice. In this study we deleted Vdr from Lrig1 expressing stem cells in the isthmus of the hair follicle then used lineage tracing to evaluate the impact on re-epithelialization following injury. We showed that Vdr deletion from these cells prevents their migration to and regeneration of the interfollicular epidermis without impairing their ability to repopulate the sebaceous gland. To pursue the molecular basis for these effects of VDR, we performed genome wide transcriptional analysis of keratinocytes from Vdr cKO and control littermate mice. Ingenuity Pathway analysis (IPA) pointed us to the TP53 family including p63 as a partner with VDR, a transcriptional factor that is essential for proliferation and differentiation of epidermal keratinocytes. Epigenetic studies on epidermal keratinocytes derived from interfollicular epidermis showed that VDR is colocalized with p63 within the specific regulatory region of MED1 containing super-enhancers of epidermal fate driven transcription factor genes such as Fos and Jun. Gene ontology analysis further implicated that Vdr and p63 associated genomic regions regulate genes involving stem cell fate and epidermal differentiation. To demonstrate the functional interaction between VDR and p63, we evaluated the response to 1,25(OH)D of keratinocytes lacking p63 and noted a reduction in epidermal cell fate determining transcription factors such as Fos, Jun. We conclude that VDR is required for the epidermal stem cell fate orientation towards interfollicular epidermis. We propose that this role of VDR involves cross-talk with the epidermal master regulator p63 through super-enhancer mediated epigenetic dynamics.
维生素 D 受体及其配体 1,25 二羟维生素 D（1,25D）调节表皮干细胞命运，使得 VDR 从 Krt14 表达的角质细胞中去除会延迟小鼠表皮创伤后再上皮化。在这项研究中，我们从毛囊峡部的 Lrig1 表达干细胞中删除了 Vdr，然后使用谱系追踪来评估对损伤后再上皮化的影响。我们表明，这些细胞中 Vdr 的缺失阻止了它们向毛囊间表皮的迁移和再生，而不损害它们再生皮脂腺的能力。为了探讨 VDR 这些作用的分子基础，我们对 Vdr cKO 和对照同窝仔鼠的角质细胞进行了全基因组转录分析。IPA 分析（IPA）指出包括 p63 在内的 TP53 家族是 VDR 的伴侣，p63 是表皮角质细胞增殖和分化所必需的转录因子。对来源于毛囊间表皮的表皮角质细胞的表观遗传学研究表明，VDR 与 p63 在包含 MED1 的特定调节区域内共定位，该区域包含驱动转录因子基因如 Fos 和 Jun 的表皮命运的超级增强子。基因本体分析进一步表明，Vdr 和 p63 相关基因组区域调节涉及干细胞命运和表皮分化的基因。为了证明 VDR 和 p63 之间的功能相互作用，我们评估了缺乏 p63 的角质细胞对 1,25（OH）D 的反应，并注意到表皮细胞命运决定转录因子如 Fos、Jun 的减少。我们得出结论，VDR 是表皮干细胞向毛囊间表皮定向所必需的。我们提出，VDR 的这种作用涉及通过超级增强子介导的表观遗传动力学与表皮主调控因子 p63 进行交叉对话。
