Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease.
Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease.
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DOI：
10.2174/1389202916666150122223252
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发表时间：
2015-04
期刊：
影响因子：
2.6
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Dharmadhikari AV;Szafranski P;Kalinichenko VV;Stankiewicz P
FOXF1 （Forkhead box F1）基因位于染色体16q24.1上，编码FOX转录因子家族的一个成员，其特征是一个独特的叉头DNA结合域。FOXF1作为Sonic hedgehog通路的下游靶点，在上皮-间质信号传导中发挥重要作用。据报道，新生儿患有致命性肺发育障碍肺泡毛细血管发育不良伴肺静脉不对准（ACDMPV）， FOXF1基因杂合点突变和基因组缺失。此外，在ACDMPV患者中发现的FOXF1上游的基因组缺失表明，FOXF1的表达受到远端组织特异性增强子的严格调控。有趣的是，已经发现FOXF1在人类肺部不完全是父系印记；特征性的基因组缺失只发生在母体16号染色体上，其中大部分是由Alu-Alu介导的。FOXF1表达的调控可能利用了染色体环、上游CpG岛重叠GLI转录因子结合位点的差异甲基化以及肺特异性长链非编码rna （lncRNAs）功能的组合。FOXF1敲除小鼠模型显示其在中胚层分化和肺血管发育中起关键作用。此外，FOXF1的表观遗传失活已在乳腺癌和结直肠癌中报道，而FOXF1的过表达与许多其他人类癌症有关，如髓母细胞瘤和横纹肌肉瘤。最近在先天性肠道畸形中报道了FOXF1的结构重复。因此，了解FOXF1位点的基因组和表观遗传复杂性将改善ACDMPV和其他与FOXF1改变相关的人类疾病的诊断、预后和治疗。
The FOXF1 (Forkhead box F1) gene, located on chromosome 16q24.1 encodes a member of the FOX family of transcription factors characterized by a distinct forkhead DNA binding domain. FOXF1 plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog pathway. Heterozygous point mutations and genomic deletions involving FOXF1 have been reported in newborns with a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed that FOXF1 expression is tightly regulated by distal tissue-specific enhancers. Interestingly, FOXF1 has been found to be incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal chromosome 16, with most of them being Alu-Alu mediated. Regulation of FOXF1 expression likely utilizes a combination of chromosomal looping, differential methylation of an upstream CpG island overlapping GLI transcription factor binding sites, and the function of lung-specific long non-coding RNAs (lncRNAs). FOXF1 knock-out mouse models demonstrated its critical role in mesoderm differentiation and in the development of pulmonary vasculature. Additionally, epigenetic inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has been associated with a number of other human cancers, e.g. medulloblastoma and rhabdomyosarcoma. Constitutional duplications of FOXF1 have recently been reported in congenital intestinal malformations. Thus, understanding the genomic and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other human disorders associated with FOXF1 alterations.