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 循环无细胞DNA（CFDNA）已彻底改变了产前诊断，但这是 冰山，作为cfDNA碎片模式嵌入了表观遗传足迹，指示了原始细胞，细胞 功能和病理状态。 cfDNA分裂，尺寸为145bp和166bp的尺寸 大约包裹在核小体周围的DNA的长度，以及核小体的连接器，其连接器， 分别。较短的片段（30-100bp）也存在，明确的周期性为10bp，对应于 围绕核心组蛋白的DNA螺旋的转弯。最近的报道表明碎片化 cfDNA的尺寸是组织特异性的，它是独特的核小体间距的产物 单个组织的功能。将这些单独的片段与现有的表观遗传数据进行比较 组织，可以简单地基于揭示核小体定位，将它们归纳为原始细胞 原始组织的信息。从母体中识别胎盘起源的CfDNA片段 循环将提供一种评估人类胎盘功能的非侵入性手段 怀孕。 几个主要障碍将CFDNA抑制为检查胎盘功能的一种非侵入性方法：1） 能够准确识别构成调节的短<160bp cfDNA片段的胎盘起源 信息（父亲SNP的发生频率约为1/2000bp）。 2）使用这些 片段将胎盘的精确表观遗传状态拼凑在一起。 3）深层基因组的成本 传统上需要对混合细胞起源的表观遗传学特征进行测序。 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提取有关人胎盘功能的精确信息的技术。我们将首先编译 来自鲁棒，准确的核小体信息，包括表观遗传和转录因子占用率，来自 人体胎盘，然后我们将建立机器学习平台，以阐明胎盘cfDNA 孕产妇循环以低成本。该项目的成功将使高风险的早期干预 怀孕并促进对怀孕的纵向实时监测 进展，从而告知自适应治疗决策。

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