The body plan of animals is laid out by an evolutionary-conserved HOX code which is colinearly transcribed after zygotic genome activation (ZGA). Here we report that SMCHD1, a chromatin-modifying enzyme needed for X-inactivation in mammals, is maternally required for timely HOX expression. Using zebrafish and mouse Smchd1 knockout animals, we demonstrate that Smchd1 haplo-insufficiency brings about precocious and ectopic HOX transcription during oogenesis and embryogenesis. Unexpectedly, wild-type offspring born to heterozygous knockout zebrafish smchd1 mothers exhibited patent vertebrate patterning defects. The loss of maternal Smchd1 was accompanied by HOX epi-mutations driven by aberrant DNA methylation. We further show that this regulation is mediated by Lrif1, a direct interacting partner of Smchd1, whose knockout in zebrafish phenocopies that of Smchd1. Rather than being a short-lived maternal effect, HOX mis-regulation is stably inherited through cell divisions and persists in cultured fibroblasts derived from FSHD2 patients haploinsufficient for SMCHD1. We conclude that maternal SMCHD1/LRIF1 sets up an epigenetic state in the HOX loci that can only be reset in the germline. Such an unusual inter-generational inheritance, whereby a phenotype can be one generation removed from its genotype, casts a new light on how unresolved Mendelian diseases may be interpreted.

动物的身体规划是由进化保守的 HOX 代码制定的，该代码在合子基因组激活 (ZGA) 后共线转录。在此，我们报道了 SMCHD1，一种哺乳动物 X 失活所需的染色质修饰酶，是母体及时表达 HOX 所必需的。使用斑马鱼和小鼠Smchd1敲除动物，我们证明 Smchd1 单倍体不足会在卵子发生和胚胎发生过程中导致早熟和异位 HOX 转录。出乎意料的是，杂合敲除斑马鱼smchd1母亲所生的野生型后代表现出明显的脊椎动物图案缺陷。母体 Smchd1 的缺失伴随着由异常 DNA 甲基化驱动的 HOX 表观突变。我们进一步表明，这种调节是由 Lrif1 介导的，Lrif1 是 Smchd1 的直接相互作用伙伴，斑马鱼中 Lrif1 的敲除与 Smchd1 的表型相似。 HOX 错误调节不是短暂的母体效应，而是通过细胞分裂稳定遗传，并持续存在于 SMCHD1 单倍体不足的 FSHD2 患者来源的培养成纤维细胞中。我们得出的结论是，母体 SMCHD1/LRIF1 在 HOX 基因座中建立了只能在种系中重置的表观遗传状态。这种不寻常的代际遗传，即表型可以从其基因型中去除一代，为如何解释未解决的孟德尔疾病提供了新的线索。