Molecular images and machine learning to extract placental function from maternal cfDNA

分子图像和机器学习从母体 cfDNA 中提取胎盘功能

• 批准号: 10359690
• 负责人: Julie C Baker
• 金额: $ 59.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-20 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359690
• 关键词: ATAC-seq; Binding; Biological Assay; Blood Circulation; Cell Extracts; Cell Size; Cell physiology; Cells; Chorionic Villi Sampling; DNA; DNA Fragmentation; DNA sequencing; Data; Decision Making; Detection; Development; Diagnostic; Early Intervention; Enhancers; Epigenetic Process; Frequencies; Genome; Genomic Segment; Genomics; Goals; High-Risk Pregnancy; Histones; Human; Image; Individual; Length; Machine Learning; Maps; Methods; Molecular; Molecular Machines; Nucleic Acid Regulatory Sequences; Nucleosomes; Pathologic; Pattern; Periodicity; Placenta; Placental Extracts; Plasma; Positioning Attribute; Pregnancy; Reporting; Techniques; Technology; Tissues; Training; Visual; base; cell free DNA; complex data; computerized data processing; cost; deep learning algorithm; denoising; epigenome; genome sequencing; image processing; molecular imaging; neural network algorithm; prenatal; promoter; real time monitoring; success; transcription factor; whole genome

Abstract Circulating cell free DNA (cfDNA) has revolutionized prenatal diagnostics, but this is the tip of the iceberg, as cfDNA fragmentation patterns embed epigenetic footprints indicative of cell of origin, cellular function and pathological state. cfDNA is fragmented with sizes centered around 145bp and 166bp which is approximately the length of DNA wrapped around a nucleosome, and a nucleosome plus its linker, respectively. Shorter fragments (30-100bp) also exist and have a clear periodicity of 10bp, corresponding to a turn of the DNA helix wrapped around the core histone. Recent reports have shown that the fragmentation sizes of cfDNA are tissue specific, which is a product of distinct nucleosome spacing that is inherent in the function of individual tissues. When these individual fragments are compared with existing epigenetic data from tissues, they can be binned into cell of origin simply based on whether they reveal the nucleosome positioning information of the originating tissue. Identifying cfDNA fragments of placental origin from maternal circulation would provide a non-invasive means of assessing placental function during human pregnancy. Several major barriers inhibit cfDNA as a non-invasive method for examining placental function: 1) the ability to accurately identify the placental origin of the short <160bp cfDNA fragments that constitute regulatory information (paternal SNPs occur at frequency of approximately 1/2000bp). 2) the ability to use these fragments to piece together precise epigenetic states of the placenta. 3) the cost of deep whole genome sequencing that has traditionally been required to deconvolute epigenetic profiles of admixed cellular origins. Our goal is to overcome each of these barriers by exploiting state-of-the-art genomics and machine learning techniques to extract precise information about human placental function from cfDNA. We will first compile robust and accurate nucleosome information, including epigenetic and transcription factor occupancy, from the human placenta and then we will establish machine-learning platforms to elucidate placental cfDNA from maternal circulation at low cost. Success in this project will enable earlier intervention for high-risk pregnancies and facilitate the longitudinal, non-invasive real-time monitoring of pregnancy progression, thereby informing adaptive treatment decision-making.

抽象的 循环游离 DNA (cfDNA) 彻底改变了产前诊断，但这只是问题的冰山一角。 冰山一角，因为 cfDNA 碎片模式嵌入了表观遗传足迹，表明细胞起源、细胞 功能和病理状态。 cfDNA 片段化，大小集中在 145bp 和 166bp 左右， 大约是包裹在核小体上的 DNA 的长度，以及核小体加上它的接头， 分别。也存在较短的片段（30-100bp），并且具有明显的 10bp 周期性，对应于 缠绕核心组蛋白的 DNA 螺旋的转角。最近的报告表明，碎片化 cfDNA 的大小是组织特异性的，这是组织中固有的不同核小体间距的产物 个体组织的功能。当这些单独的片段与现有的表观遗传数据进行比较时 组织，可以简单地根据它们是否揭示核小体定位将它们分类到起源细胞中 原始组织的信息。鉴定母体胎盘来源的 cfDNA 片段 循环将提供一种非侵入性的方法来评估人类妊娠期间的胎盘功能。 怀孕。 cfDNA 作为检查胎盘功能的非侵入性方法有几个主要障碍：1) 能够准确识别构成监管的 <160bp cfDNA 短片段的胎盘来源 信息（父本 SNP 出现的频率约为 1/2000bp）。 2）使用这些的能力 碎片将胎盘的精确表观遗传状态拼凑在一起。 3）深度全基因组的成本 传统上需要对混合细胞起源的表观遗传图谱进行解卷积测序。 我们的目标是通过利用最先进的基因组学和机器学习来克服这些障碍 从 cfDNA 中提取有关人类胎盘功能的精确信息的技术。我们首先会编译 强大而准确的核小体信息，包括表观遗传和转录因子占用，来自 人类胎盘，然后我们将建立机器学习平台来阐明胎盘cfDNA 母体循环成本低。该项目的成功将使高风险的早期干预成为可能 妊娠并促进妊娠的纵向、无创实时监测 进展，从而为适应性治疗决策提供信息。

项目成果

Uterine injury during diestrus leads to placental and embryonic defects in future pregnancies in mice†.

发情间期的子宫损伤会导致小鼠在未来怀孕时出现胎盘和胚胎缺陷。

• DOI: 10.1093/biolre/ioae001
• 发表时间: 2024
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Zhang,ElisaT;Wells,KristenL;Bergman,AbbyJ;Ryan,EmilyE;Steinmetz,LarsM;Baker,JulieC
• 通讯作者: Baker,JulieC