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Defining Activities of KDMS Essential to Development and Viability

定义对发展和生存至关重要的 KDMS 活动

基本信息

批准号：
10672661
负责人：
Melissa Castiglione
金额：
$ 4.77万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-30 至 2026-03-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672661
关键词：
Address Adult Alleles Amino Acid Sequence Amino Acids Animals Binding Biological Models C-terminal Characteristics Chromatin Chromatin Remodeling Factor Conserved Sequence Control Animal Data Defect Development Developmental Delay Disorders Disease Drosophila genus Family Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Gland Goals Histones Homologous Gene Human Intellectual functioning disability Knowledge Label Lysine Malignant Neoplasms Mediating Methylation Molecular Neurosecretory Systems Nonsense Mutation Pathway interactions Phenotype Play Point Mutation Protein Family Protein Region Proteins Proteomics Publishing Regulation Regulator Genes Role Structure Study models Terminator Codon Testing Tissues Work alpha helix design feature detection fly histone demethylase in vivo molecular recognition mutant neuron development novel paralogous gene programs protein protein interaction recruit targeted treatment tool transcriptome sequencing transcriptomics

项目摘要

ABSTRACT The Lysine demethylase 5 (KDM5) family of transcriptional regulators are important for normal development, and their dysregulation is a key driver of intellectual disability and several forms of cancer. Most work to-date has focused on the histone demethylase activity of KDM5 proteins, which targets the active chromatin mark H3K4me3. However, KDM5 proteins can also regulate transcription through non-enzymatic mechanisms. While KDM5 is essential for development, its demethylase activity is not required, as is demonstrated by the viability of demethylase-dead adult flies. In this work, we will examine essential functions of KDM5 via a novel truncation allele, kdm5Q19, which does not alter demethylase activity. kdm5Q19 inserts a stop codon in a previously unrecognized, evolutionarily conserved, motif within an intrinsically disordered region of KDM5 at the C-terminus. kdm5Q19 animals do not survive to adulthood, which is distinct from null, demethylase dead, and other mutants generated in our lab, suggesting that the motif disrupted by the truncation has an essential as-yet-unknown role in normal KDM5 function. To further dissect the molecular activities of this region of KDM5, we generate additional alleles of kdm5 to refine the critical region(s) of the protein and assess viability and changes to transcription. In this work, we will (1) define essential regions within KDM5 required for viability, and to characterize their roles in development (2) define the essential molecular functions imparted by the C-terminus of KDM5. Together, these studies will refine the critical region(s) of the C-terminus of KDM5, and define the normal role of these regions in regulating transcription.

摘要赖氨酸脱甲基酶5（KDM 5）家族的转录调节因子对于正常发育是重要的，它们的失调是智力残疾和几种癌症的关键驱动因素。大多数工作至今 KDM 5蛋白质的组蛋白去甲基化酶活性，其靶向活性染色质标记 H3K4me3.然而，KDM 5蛋白也可以通过非酶机制调节转录。而 KDM 5对于发育是必需的，其脱甲基酶活性不是必需的，如由KDM 5的活力所证明的。去甲基化酶致死的成年苍蝇。在这项工作中，我们将通过一种新的截断来研究KDM 5的基本功能等位基因，kdm 5 Q19，其不改变脱甲基酶活性。kdm 5 Q19将终止密码子插入先前的未识别的，进化上保守的，基序在KDM 5的C-末端的固有无序区域内。 kdm 5 Q19动物不能存活至成年期，这与null、去甲基酶死亡和其他突变体不同在我们的实验室中产生，这表明被截断破坏的基序具有重要的迄今未知的作用正常的KDM 5功能。为了进一步剖析KDM 5这一区域的分子活性，我们生成了 kdm 5的其他等位基因，以细化蛋白质的关键区域并评估存活力和变化，转录。在这项工作中，我们将（1）定义KDM 5中可行性所需的基本区域，并描述它们的作用在开发（2）中定义了KDM 5的C-末端赋予的基本分子功能。在一起，这些研究将完善KDM 5 C末端的关键区域，并确定这些区域的正常作用。转录调控区。