PDF(Pubmed)
Abstract：
Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.
摘要：
分裂手/足畸形3型（SHFM3）是先天性肢体畸形，与LBX1/FGF8基因座的串联重复有关。然而，该疾病的病理机制仍未解决。在这里，我们研究了SHFM3相关重排对转基因小鼠体内染色质构象和基因表达的功能影响。我们表明Lbx1/Fgf8基因座由两个独立的，但是相互作用，监管域。在小鼠中重新设计SHFM3相关的重复和新报道的倒置导致染色质结构的重构。这导致根尖外胚层脊（AER）中的Lbx1和Btrc基因以Fgf8的AER特异性增强子诱导的Fgf8样模式异位激活。我们提供的证据表明，SHFM3表型是对发育中肢体中基因错误表达的组合效应的结果。我们的结果揭示了SHFM3潜在的分子机制，并为基因组重排如何导致基因错误表达和疾病提供了概念框架。
