Investigating How Defects in The Maternal Germline Reprogramming of Histone Methylation Contribute to Inherited Disease

研究母体种系组蛋白甲基化重编程缺陷如何导致遗传性疾病

• 批准号: 10592730
• 负责人: David John Katz
• 金额: $ 38.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592730
• 关键词: Address; Affect; Alleles; Animals; Behavioral; Brain Stem; Caenorhabditis elegans; Cell division; Cells; Cellular biology; Child; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Craniofacial Abnormalities; DNA; Data; Defect; Developmental Delay Disorders; Disease; Embryo; Enzymes; Epigenetic Process; Exhibits; Failure; Fertilization; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genomic Imprinting; Genomics; Germ Cells; Germ Lines; Hereditary Disease; Heritability; Histones; Human; Inherited; Intellectual functioning disability; KDM1A gene; Kabuki Make-Up Syndrome; Lead; Learning; Longevity; Mammals; Maternal Age; Memory; Methylation; Methyltransferase; Modeling; Mus; Mutate; Mutation; Neurodevelopmental Disorder; Oocytes; Pathway interactions; Patients; Pattern; Perinatal mortality demographics; Phenotype; Predisposition; Reporter; SETDB1 gene; Sterility; Symptoms; Testing; base; experimental study; genome-wide; histone methylation; human disease; imprint; methylation pattern; mouse model; neuromuscular; next generation; novel; prevent; repetitive behavior

Patterns of histone methylation can be propagated through cell division as a form of transcriptional memory to maintain transcriptional states. At fertilization, this histone methylation must be reprogrammed to prevent the inappropriate inheritance of transcriptional states in the progeny. My lab has shown in both C. elegans and mice, that lack of reprogramming histone methylation at fertilization can lead to the epigenetic inheritance of abnormal phenotypes. These phenotypes are reminiscent of defects observed in patients with mutations in the H3K4me1/2 demethylase LSD1/KDM1A, and in Kabuki Syndrome, caused by mutations in other histone modifying enzymes. This raises the possibility that maternal germ line reprogramming may be a susceptibility point through which human mutations in histone modifying enzymes contribute to human disease. To investigate this possibility my lab has generated a new hypomorphic allele of LSD1 in mouse oocytes. In this proposal, we will use this new LSD1 mouse to address the following questions. Can hypomorphic maternal LSD1 at fertilization lead to developmental delay and learning deficits observed in human LSD1 patients and Kabuki Syndrome patients? How does maternal age and genetic background modulate phenotypes caused by hypomorphic maternal LSD1? Does LSD1 cooperate in maternal reprogramming with the H3K9 methyltransferase SETDB1? What is the mechanism through which maternal loss of LSD1 contributes to inherited defects? What are the genes/pathways that are affected by maternal loss of LSD1? How does hypomorphic LSD1 at fertilization affect imprinted gene expression? Addressing these questions will begin to determine whether defects in maternal epigenetic reprogramming can contribute to inherited human disease.

组蛋白甲基化的模式可以通过细胞分裂传播，作为转录记忆的一种形式 保持转录状态。受精时，必须对这种组蛋白甲基化进行重编程，以防止 后代转录状态的不当继承。我的实验室已经在秀丽隐杆线虫和 小鼠，缺乏受精时缺乏重编程组蛋白甲基化会导致表观遗传 异常表型。这些表型让人想起在突变患者中观察到的缺陷 H3K4ME1/2脱甲基酶LSD1/KDM1A和Kabuki综合征，由其他组蛋白突变引起 修饰酶。这增加了母体种系重编程可能是一种敏感性的可能性 组蛋白中的人类突变修饰酶有助于人类疾病。到 研究这种可能性，我的实验室已经在小鼠卵母细胞中产生了新的LSD1的肌科等位基因。在这个 提案，我们将使用此新的LSD1鼠标来解决以下问题。可以造生母亲 受精时的LSD1导致人类LSD1患者观察到的发育延迟和学习缺陷， Kabuki综合征患者？产妇的年龄和遗传背景如何调节由 型母亲LSD1？ LSD1是否与H3K9进行孕妇重编程合作 甲基转移酶SetDB1？ LSD1的产妇损失有助于什么机制 继承的缺陷？ LSD1损失影响的基因/途径是什么？怎么样 受精时的肌lsd1会影响印迹基因表达？解决这些问题将开始 确定母体表观遗传重编程中的缺陷是否会导致遗传性人类疾病。