Pediatric Neuroendocrinology Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, USA.
Integrative Bioinformatics, NIEHS, Research Triangle Park, NC, USA.
Sci Adv. 2023 Feb 17;9(7):eabq7744. doi: 10.1126/sciadv.abq7744.
mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.
突变导致先天性无鼻畸形（无鼻）和一种称为 FSHD2 的肌肉营养不良症。在 FSHD2 中，SMCHD1 抑制活性的丧失导致双同源框 4（DUX4）在肌肉组织中表达，在那里它是有毒的。对无鼻畸形患者的研究表明，鼻基板细胞（人鼻祖细胞）存在主要缺陷。在这里，我们表明，在 SMCHD1 缺失后，当 H9 人胚胎干细胞（hESC）向基板细胞命运分化时，DUX4 被解除抑制，引发细胞死亡。当转化为基板细胞时，无鼻畸形和 FSHD2 患者来源的诱导多能干细胞（iPSC）表达 DUX4，并表现出不同程度的细胞死亡，表明存在环境疾病修饰因子。单纯疱疹病毒 1 可能是这样的修饰因子之一，因为疱疹病毒感染会扩增 SMCHD1 KO hESC 和患者 iPSC 中的 DUX4 表达。这些研究表明，无鼻畸形与 FSHD2 一样，是由于特定细胞中 SMCHD1 抑制活性受损引起的，并为环境修饰因子提供了证据。
