Metabolic control of global gene expression during the Maternal-to-Zygotic Transition

母体向合子转变期间整体基因表达的代谢控制

• 批准号: 10542564
• 负责人: Lital Bentovim
• 金额: $ 3.82万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542564
• 关键词: ATAC-seq; Animal Model; ChIP-seq; Chromatin; DNA; Data; Development; Developmental Gene; Developmental Process; Diabetes Mellitus; Disease; Drosophila genus; Embryo; Enzymes; Gene Abnormality; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic approach; Global Change; Goals; Histones; Human; Image; Lead; Link; Malignant Neoplasms; Mass Spectrum Analysis; Maternal Messenger RNA; Measures; Messenger RNA; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolism; Methods; Methylation; Modification; Molecular Genetics; Paint; Play; Process; RNA; RNA Interference; Regulation; Reporter; Research; Research Personnel; Resolution; Role; Shapes; Signal Transduction; System; Testing; Therapeutic Intervention; Time; Transcript; Transcriptional Activation; Western Blotting; Zebrafish; alpha ketoglutarate; demethylation; egg; experimental study; genetic approach; histone methylation; histone modification; human disease; in vivo; mRNA Decay; mRNA Transcript Degradation; metabolic abnormality assessment; mutant; novel; programs; skills; targeted treatment; tool; transcriptome; transcriptome sequencing

ABSTRACT After an egg is fertilized, many thousands of genes are turned on in the embryo while maternal mRNA is degraded; this process is called the maternal-to-zygotic transition (MZT). The goal of this proposal is to decipher how activation of zygotic genes is synchronized with maternal mRNA decay. Both histone modifications and the mRNA modification N6-methyladenosine (m6A) play prominent roles, during the MZT, by regulating transcription of zygotic genes and maternal mRNA clearance, respectively. However, the signals that control changes in chromatin and mRNA modifications in this critical developmental stage are largely unknown. This proposal will test the novel hypothesis that changes in cellular metabolism coordinate global gene expression during the MZT, through modulating the availability of metabolites required for chromatin and mRNA modifications. Using high-resolution mass-spectrometry, in Drosophila (D). melanogaster embryos during the MZT, we identified changes in the levels of alpha-ketoglutarate (α-KG), which is a required co-factor for histone and RNA demethylation enzymes. Here, we test our central hypothesis through the following specific aims: (1) test the link between α-KG levels, histone methylation, and global transcription activation of zygotic genes, and (2) test the link between α-KG levels, m6A modification of mRNA, and maternal mRNA decay. D. melanogaster embryos are an ideal system for studying the interplay between metabolism and gene regulation because there are many experimental tools for manipulating and measuring metabolism, chromatin state, mRNA modifications and transcription in vivo. This proposal will apply molecular, genetic and genomic approaches to demonstrate how metabolic inputs, such as α-KG, shape the developmental transcriptome and coordinate critical developmental processes by controlling both chromatin and mRNA modifications. Findings from this study will be relevant for understanding not only developmental processes but also diseases in which metabolic dysfunction is associated with abnormal gene expression, such as cancer and diabetes. Establishing D. melanogaster as an experimental platform for studying metabolic regulation of global gene expression and acquiring the relevant set of skills as part of this research plan will be a critical next step towards fulfilling my goal of becoming an independent investigator.

摘要