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.

组蛋白甲基化模式可以通过细胞分裂作为转录记忆的一种形式传播到 保持转录状态。受精时，这种组蛋白甲基化必须重新编程，以防止 在后代中转录状态的不适当遗传。我的实验室发现了线虫和线虫 受精时缺乏重新编程的组蛋白甲基化可导致表观遗传 异常表型。这些表型让人想起在基因突变患者中观察到的缺陷 H3K4me1/2去甲基酶LSD1/KDM1A，以及歌舞伎综合症，由其他组蛋白突变引起 修饰酶。这增加了母体生殖系重新编程可能是一种易感性的可能性 人类组蛋白修饰酶突变导致人类疾病的时间点。至 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一种新的LSD1亚型等位基因。在这 提案中，我们将使用这个新的LSD1鼠标来解决以下问题。亚形母体可以吗 受精时LSD1导致人类LSD1患者发育迟缓和学习障碍 歌舞伎症患者？母亲的年龄和遗传背景如何调节由B型流感引起的表型 亚形母体LSD1？LSD1是否与H3K9合作进行母体重新编程 甲基转移酶SETDB1？母体LSD1缺失是通过什么机制导致的 遗传缺陷？母体LSD1缺失会影响哪些基因/途径？何以 受精时LSD1亚型会影响印记基因表达吗？解决这些问题将开始 确定母体表观遗传重编程缺陷是否会导致遗传性人类疾病。