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Function of Kdm4dl-mediated heterochromatin removal in the preimplantation mouse embryo

Kdm4dl 介导的植入前小鼠胚胎异染色质去除的功能

基本信息

批准号：
10540694
负责人：
Sean Shadle
金额：
$ 7.18万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540694
关键词：
Ablation Address Affect Animals Area Assisted Reproductive Technology Auxins Biological Assay Cancer Biology Cell Line Cell Nucleus Cells Chimera organism Chromatin Chromatin Modeling Code Complement Data Deposition Development Developmental Process Doxycycline Embryo Embryonic Development Environment Epigenetic Process Excision Fertility Fertilization Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Epistasis Genetic Transcription Genome Goals Health Heterochromatin Histones Human Immunofluorescence Immunologic Knock-out Knockout Mice Lysine Mediating Methylation Modeling Mus Orthologous Gene Pathway interactions Pattern Phenotype Placenta Pre-implantation Embryo Development Process Productivity Proteins Research Personnel Research Project Grants Role System Testing Time Totipotency Totipotent Training Transcript Transcriptional Activation Transgenes Untranslated RNA blastocyst blastomere structure chromatin remodeling demethylation egg embryo cell embryonic stem cell histone demethylase histone modification in vivo innovation mouse model novel overexpression placental mammal preimplantation programs protein expression transcription factor transcriptome sequencing zygote

项目摘要

PROJECT ABSTRACT This project will investigate the function of a currently unstudied histone demethylase, Kdm4dl, in the mouse preimplantation embryo. Many others have shown the developmental importance of activating genes and repeat sequences during a process known as Embryonic Genome Activation (EGA), the moment when the embryo switches on transcription for the first time. EGA involves activation of both protein coding genes as well as repeat sequences that are critical for remodeling the chromatin environment of the early embryo. Yet, even with its known developmental importance, the factors which facilitate EGA are still largely unknown. Here, for the first time, I will investigate the importance of Kdm4dl, which catalytically removes the repressive histone modification H3 Lysine 9 tri-methylation (H3K9me3), in early mouse embryogenesis. I hypothesize that Kdm4dl is required for reprogramming the nuclei of the preimplantation embryo by removing repressive H3K9me3, which facilitates strong activation of EGA-associated transcripts. In line with this hypothesis, my preliminary data demonstrate temporally coordinated Kdm4dl protein expression during the 2-cell stage, when EGA occurs. Moreover, Kdm4dl over-expression is sufficient to demethylate H3K9me3 in embryonic stem cells leading to strong activation of EGA-associate transcripts and repeats. Combined, these preliminary data provide further support for pursuing the project’s hypothesis further. The two outstanding questions I aim to address are: 1. Is Kdm4dl expression sufficient to reprogram cells to a state of expanded potential, consistent with a 2-cell-like totipotent state? and 2. Is Kdm4dl expression necessary for H3K9 demethylation and activation of EGA-associated genes and repeats in vivo? To aid in addressing these questions, I have developed both an innovative embryonic stem cell system which recapitulates the temporal dynamics of Kdm4dl expression in the preimplantation embryo, and I have also established a Kdm4dl knockout mouse model. This research project, combined with my detailed training plan, is consistent with my technical and professional goals of becoming an independent academic investigator studying chromatin dynamics in the early mammalian embryo, with relevance to human fertility.

项目摘要