Epigenetic control of developmental gene regulation

发育基因调控的表观遗传控制

• 批准号: 10735218
• 负责人: THOMAS G FAZZIO
• 金额: $ 48.21万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735218
• 关键词: Affect; Atlases; Benchmarking; Binding; Binding Proteins; Binding Sites; Biogenesis; Biological; CCCTC-binding factor; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Chromosomes; Code; DNA; Data; Defect; Deposition; Development; Developmental Gene; ES Cell Line; Embryo; Embryonic Development; Epigenetic Process; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic Instability; Genotoxic Stress; Germ Layers; Heterogeneity; Hybrids; Impairment; Location; Maintenance; Maps; Mediating; Mediator; Meditation; Methods; Methylation; Methyltransferase; Modeling; Mus; Nuclear RNA; Nuclear Structure; Pathway interactions; Play; Process; Proteins; RNA; RNA Processing; RNA Splicing; Regulation; Research; Ribosomal DNA; Ribosomes; Role; Specific qualifier value; Structure; Testing; Transcript; Transcription Elongation; Transcription Initiation; Untranslated RNA; cell type; cohesin; developmental disease; embryonic stem cell; epigenetic profiling; epigenome; epigenomic profiling; experimental study; gastrulation; gene regulatory network; genomic tools; histone modification; in vivo; novel; progenitor; protein function; recruit; stem cell differentiation; tool; transcription factor; transcriptome sequencing

PROJECT SUMMARY Although multiple epigenetic processes contribute to developmental gene regulation, the mechanisms by which they rewire gene regulatory networks during lineage specification are often unclear. Defects in epigenetic gene regulation contribute to developmental disorders and disease. Nuclear RNAs, including multiple classes of non-coding RNAs and nascent transcripts of coding genes help regulate the epigenetic landscape and facilitate developmental gene regulation. We have focused on the functions of R-loops—RNA/DNA hybrids that most often arise when nascent transcripts hybridize to their DNA templates—in the control of epigenetic gene regulation in mouse embryonic stem cells (mESCs). We previously discovered that R-loops modulate binding of the Tip60-p400 chromatin remodeling complex and partial depletion of R-loops from mESCs impairs the fidelity of differentiation. However, the precise roles of R-loops in differentiation are unclear. We have recently taken systematic and unbiased approaches to identify how R-loops impact the epigenome of mESCs and uncover how depletion of R-loops disrupts differentiation. In addition, we uncovered R-loop binding proteins that likely mediate some of their regulatory functions. We further developed new, single-cell genomic tools necessary to uncover how R-loops and other classes of nuclear RNAs meditate their effects in different lineages. Here, we propose to characterize the effects of one novel R-loop binding protein that functions in gene regulation and is essential for cell proliferation. In addition, we will examine the roles of R-loops in transcription elongation, fidelity, and RNA processing. Finally, we will leverage novel tools we developed for simultaneous profiling of epigenetic features to identify the locations of R-loops and epigenetic marks during gastrulation, where the three primary germ layers are established from pluripotent progenitors. Drawing on this in vivo atlas, we will use an inducible RNaseH1 mESC line to disrupt R-loops in an ESC differentiation model, uncovering their cell type-specific targets and mechanisms by which they control developmental gene expression. Together, these studies will uncover the functions of a key mediator of R-loop dependent gene regulation, the mechanisms by which R-loops modulate epigenetic marks critical for transcriptional fidelity, and the developmental targets of R-loops. These studies will significantly expand our understanding of RNA- mediated gene regulation and its roles in establishment of the mammalian body plan.

项目总结 尽管多个表观遗传过程有助于发育基因调控，但其机制 它们在谱系指定期间重新连接基因调控网络通常是不清楚的。表观遗传基因缺陷 监管会导致发育障碍和疾病。核RNA，包括多种类型的 非编码RNA和编码基因的新生转录本有助于调节表观遗传格局并促进 发育基因调控。我们重点介绍了R-环-RNA/DNA杂交体的功能 通常发生在新生转录体与其DNA模板杂交时-在表观遗传基因的控制下 小鼠胚胎干细胞的调控。我们之前发现，R环调节结合 Tip60-P400染色质重塑复合体的表达和部分去除小鼠胚胎干细胞的R环 差异化的保真度。然而，R环在分化中的确切作用尚不清楚。我们最近做了 采取系统和公正的方法来确定R-环如何影响mESCs的表观基因组和 揭示R环的耗尽是如何破坏分化的。此外，我们还发现了R-环结合蛋白 这可能会调停它们的一些监管职能。我们进一步开发了新的单细胞基因组工具 有必要揭示R-环和其他类型的核RNA是如何在不同的 血统。在这里，我们建议表征一种新的R-环结合蛋白的作用，该蛋白在 基因调控，对细胞增殖至关重要。此外，我们还将研究R-环在 转录延伸、保真度和RNA处理。最后，我们将利用我们为其开发的新工具 同时分析表观遗传特征以确定R-环和表观遗传标记的位置 原肠形成，其中三个初级胚层是由多能祖细胞建立的。在这上面画画 在活体图谱中，我们将使用可诱导的RNaseH1 mESC系来干扰ESC分化模型中的R环， 揭示它们的细胞类型特异性靶点和它们控制发育基因的机制 表情。总之，这些研究将揭示R环依赖基因的一个关键中介的功能 调节，R-环调节对转录保真度至关重要的表观遗传标记的机制，以及 R环的发展目标。这些研究将极大地扩展我们对RNA- 介导的基因调控及其在哺乳动物体型计划制定中的作用。

项目成果

Preface.

前言。

• DOI: 10.1016/s1877-1173(16)30035-7
• 发表时间: 2016
• 期刊: Progress in molecular biology and translational science
• 作者: Shenoy,SudhaK

S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress.

• DOI: 10.7554/elife.79511
• 发表时间: 2023-02-09
• 期刊: eLife
• 影响因子: 7.7
• 作者: Godbole AA;Gopalan S;Nguyen TK;Munden AL;Lui DS;Fanelli MJ;Vo P;Lewis CA;Spinelli JB;Fazzio TG;Walker AK
• 通讯作者: Walker AK

An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5.

• DOI: 10.1016/j.stemcr.2017.04.020
• 发表时间: 2017-06-06
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Ee LS;McCannell KN;Tang Y;Fernandes N;Hardy WR;Green MR;Chu F;Fazzio TG
• 通讯作者: Fazzio TG

Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1.

• DOI: 10.1038/s41467-023-36035-9
• 发表时间: 2023-01-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Conti, Michelle M.;Li, Rui;Narvaez Ramos, Michelle A.;Zhu, Lihua Julie;Fazzio, Thomas G.;Benanti, Jennifer A.
• 通讯作者: Benanti, Jennifer A.

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.

EZH2抑制重塑了炎症性衰老相关的分泌表型，以增强胰腺癌免疫监测。

• DOI: 10.1038/s43018-023-00553-8
• 发表时间: 2023-06
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Chibaya, Loretah;Murphy, Katherine C. C.;DeMarco, Kelly D. D.;Gopalan, Sneha;Liu, Haibo;Parikh, Chaitanya N. N.;Lopez-Diaz, Yvette;Faulkner, Melissa;Li, Junhui;Morris, John P. P.;Ho, Yu-jui;Chana, Sachliv K. K.;Simon, Janelle;Luan, Wei;Kulick, Amanda;de Stanchina, Elisa;Simin, Karl;Zhu, Lihua Julie;Fazzio, Thomas G. G.;Lowe, Scott W. W.;Ruscetti, Marcus
• 通讯作者: Ruscetti, Marcus