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

基本信息

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
项目类别：
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

项目摘要

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 的表观基因组功能障碍——血管缺陷和围产期后果。抽象的 FOXF1 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)，一种新生儿致命的发育性肺病。大多数 ACDMPV 患者还有涉及心脏、胃肠道或泌尿生殖系统的其他缺陷在内皮细胞和平滑肌细胞中表达的间充质 FOXF1 转录因子。作为 Sonic Hedgehog 的下游靶点，在上皮间质信号传导中发挥重要作用最近，我们积累了世界上最大的ACDMPV样本集（N~145个家族）。我们发现基因组缺失映射在 FOXF1 上游约 270 kb 的蛋白质编码基因荒漠中，保留完整的 ACDMPV 表型。这些删除使我们能够定义约 60 kb 的内容。含有长非编码 RNA (lncRNA)、LINC01081 和 LINC01082 的组织特异性增强子区域，另一种 lncRNA FENDRR 表达于 FOXF1 上游 1.7 kb 处。方向并可能利用与 FOXF1 相同的双向启动子，与染色质修饰相互作用复合体 (PRC) 2 象征性地调节基因表达，Fendrr 纯合缺失，使 Foxf1 完好无损，导致小鼠新生儿肺部和心脏的致命缺陷，重要的是，我们发现 FOXF1 基因座是。印记，可能使用这些 lncRNA；31/32 的特征性基因组缺失是在母体上重新出现的；人类染色体 16q24.1，由母体减数分裂 I 不分离导致，是最常见的。常见的产前三体性（>所有妊娠的 1%），除非在胚胎早期抢救，否则致命。在此类病例中，患有母亲 UPD(16) 的儿童表现出 IUGR（归因于三体胎盘）和多发性先天性畸形，包括心脏缺陷、肺发育不全、气管食管瘘、肠道旋转不良、胆囊缺如、肾发育不全、肾积水、肛门闭锁和单脐动脉。暗示，除 IUGR 外，所有上述临床特征均在绝大多数患有此病的儿童中观察到。相反，在少数患有父亲 UPD 的患者中报告了相对正常的表型 (16)，并且 16 号染色体上的印记基因被认为是母体 UPD(16) 表型的致病因素。 FOXF1 增强子和 lncRNA 在 16q24.1 的基因组印记中发挥重要作用，这可能是母体 UPD 的关键特征(16) 在目标 1 中，我们将研究基因组的作用。 ACDMPV 和 UPD 中 FOXF1 基因座的印记在目标 2 中，我们将分析 FOXF1 的功能。增强子，包括重叠的lncRNA 在目标3中，我们将研究FENDRR在其中的功能。拟议的研究将提供更好的心脏、肺和胎盘的发育和疾病。了解远距离组织特异性增强子在基因组印记中的功能及其发展该提案还将阐明 lncRNA 在增强子功能和基因调控中的作用。总体而言，并提供有关此类有希望的治疗靶点的知识。