Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences

16q24.1 血管缺陷的表观基因组功能障碍和围产期后果

• 批准号: 9287627
• 负责人: PAWEL STANKIEWICZ
• 金额: $ 48.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-22 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287627
• 关键词: Address; Alveolar capillary dysplasia with misalignment of pulmonary veins; Blood Vessels; Cardiac; Child; Chromatin; Chromosomes; Chromosomes, Human, Pair 16; Clinical; Code; Collection; Complex; Congenital Abnormality; Defect; Deletion Mutation; Development; Diffuse; Disease; Distant; Embryo; Enhancers; Epigenetic Process; Epithelium; FOXF1 gene; Family; Fetal Growth Retardation; Fetal Lung; Fistula; Functional disorder; Gallbladder; Gene Expression; Gene Expression Regulation; Genes; Genetic Nondisjunction; Genitourinary system; Genomic Imprinting; Genomics; Heart; Heart Abnormalities; Heart Diseases; Human; Human Cell Line; Hydronephrosis; Hypoplastic Left Heart Syndrome; Imperforate Anus; Junk DNA; Knock-out; Knowledge; Lead; Ligands; Lung; Lung diseases; Maps; Maternal uniparental disomy; Meiosis; Mesenchymal; Mesenchyme; Methylation; Molecular; Molecular Conformation; Mus; Neonatal; Online Mendelian Inheritance In Man; Parents; Patients; Perinatal; Phenotype; Placenta; Placenta Diseases; Play; Point Mutation; Pregnancy; Process; Proteins; Regulation; Regulator Genes; Reporting; Role; Sampling; Signal Transduction; Smooth Muscle Myocytes; Sonic Hedgehog Pathway; Structure of umbilical artery; Tissues; Trisomy; Trisomy 16; Untranslated RNA; Upstream Enhancer; base; cardiogenesis; developmental disease; epigenomics; gastrointestinal system; genome-wide; imprint; lung development; neonate; prenatal; promoter; pulmonary hypoplasia; renal agenesis; spatiotemporal; therapeutic target; transcription factor; transcriptome

Epigenomic dysfunction at 16q24.1 – vascular defects and perinatal consequences. ABSTRACT Heterozygous genomic deletions and point mutations in the FOXF1 cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV), a neonatally lethal developmental lung disease. The vast majority of ACDMPV patients have additional defects involving heart, gastrointestinal, or genitourinary systems. The mesenchymal FOXF1 transcription factor expressed in the endothelial and smooth muscle cells plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog pathway. We accumulated the largest collection of ACDMPV samples in the world (N~145 families). Recently, we found that genomic deletions mapping in a protein-coding gene desert ~270 kb upstream to FOXF1 and leaving it intact manifest with the full ACDMPV phenotype. These deletions enabled us to define an ~60 kb tissue-specific enhancer region harboring long non-coding RNAs (lncRNAs), LINC01081 and LINC01082, that are expressed in fetal lungs. Another lncRNA, FENDRR that maps 1.7 kb upstream of FOXF1 in the opposite orientation and likely utilizes the same bi-directional promoter as FOXF1, interacts with chromatin-modifying complex (PRC) 2 to regulate gene expression. Interestingly, homozygous loss of Fendrr, leaving Foxf1 intact, leads to lethal defects of lungs and heart in mouse neonates. Importantly, we found that the FOXF1 locus is imprinted, likely using these lncRNAs; 31/32 of the characterized genomic deletions arose de novo on maternal chromosome 16q24.1. Trisomy 16 in humans, resulting from maternal meiosis I nondisjunction, is the most common prenatal trisomy (>1% of all pregnancies) and lethal unless rescued early embryonically. In one-third of such cases, children with maternal UPD(16) manifest IUGR (attributed to trisomic placenta) and multiple congenital malformations, including heart defects, pulmonary hypoplasia, tracheosophageal fistula, gut malrotation, absent gall bladder, renal agenesis, hydronephrosis, imperforate anus, and single umbilical artery. Interestingly, all the above clinical features, except IUGR, are observed in the vast majority of children with ACDMPV. In contrast, relatively normal phenotype was reported in few patients with paternal UPD(16), and imprinted gene(s) on chromosome 16 were suggested as causative for maternal UPD(16) phenotype. We hypothesize that FOXF1 enhancer and lncRNAs play an important role in genomic imprinting at 16q24.1, which may be responsible for the key features of maternal UPD(16). In aim 1, we will study the role of genomic imprinting of the FOXF1 locus in ACDMPV and UPD(16). In aim 2, we will analyze the function of the FOXF1 enhancer, including the overlapping lncRNAs. In aim 3, we will investigate the function of FENDRR in development and disease of heart, lung, and placenta. The proposed studies would provide a better understanding of the function of distant tissue-specific enhancers in genomic imprinting and the development and disease. This proposal would also elucidate the role of lncRNAs in enhancer function and gene regulation in general, and provide knowledge on this class of promising therapeutic targets.

16q24.1表观基因组功能障碍-血管缺陷和围产期后果。 摘要 FOXF 1的杂合基因组缺失和点突变导致肺泡毛细血管发育不良， 肺静脉错位（ACDMPV），一种致死性发育性肺病。绝 大多数ACDMPV患者有其他涉及心脏、胃肠道或泌尿生殖系统的缺陷 系统.间充质FOXF 1转录因子在血管内皮细胞和平滑肌细胞中的表达 作为Sonic hedgehog的下游靶点，在上皮-间充质信号转导中起重要作用 通路我们积累了世界上最大的ACDMPV样品库（N~145个家庭）。最近， 我们发现FOXF 1上游约270 kb的蛋白质编码基因缺失， 留下完整的ACDMPV表型。这些删除使我们能够定义一个~60 kb的 携带长非编码RNA（lncRNA）LINC 01081和LINC 01082的组织特异性增强子区， 在胎儿肺中表达。另一种lncRNA，FENDRR，定位于相反方向FOXF 1上游1.7 kb处 可能利用与FOXF 1相同的双向启动子，与染色质修饰 复合物（PRC）2调节基因表达。有趣的是，Fendrr的纯合缺失，留下Foxf 1完整， 导致小鼠新生儿肺和心脏致命缺陷。重要的是，我们发现FOXF 1基因座是 印迹，可能使用这些lncRNA; 31/32的特征性基因组缺失在母体上从头出现。 染色体16q24.1。人类16号三体是由母体减数分裂I不分离引起的， 常见的产前三体性（>1%的所有怀孕）和致命的，除非抢救早期胚胎。在三分之一 在这些病例中，母亲患有UPD的儿童（16）表现为IUGR（归因于三体胎盘）和多个 先天性畸形，包括心脏缺陷、肺发育不全、气管食管瘘、肠 旋转不良、胆囊缺如、肾发育不全、肾积水、无肛和单脐动脉。 有趣的是，除IUGR外，所有上述临床特征在绝大多数患有IUGR的儿童中观察到。 ACDMPV。相比之下，在少数父亲UPD患者中报告了相对正常的表型（16）， 16号染色体上的印记基因被认为是导致母体UPD（16）表型的原因。我们 假设FOXF 1增强子和lncRNA在16q24.1基因组印记中起重要作用， 可能是导致母体UPD的关键特征的原因（16）。在目标1中，我们将研究基因组的作用， ACDMPV和UPD中FOXF 1基因座的印记（16）。在目标2中，我们将分析FOXF 1的功能 增强子，包括重叠的lncRNA。在目的3中，我们将研究FENDRR的功能， 心脏、肺和胎盘的发育和疾病。拟议的研究将提供一个更好的 远缘组织特异性增强子在基因组印迹中的作用及其研究进展 和疾病这一提议也将阐明lncRNA在增强子功能和基因调控中的作用。 并提供关于这类有前途的治疗靶点的知识。