COORDINATE REGULATION BY MAP3K4 OF EPIGENETIC MODIFIERS CONTROLLING EMT

MAP3K4 对控制 EMT 的表观遗传修饰子的协调调控

基本信息

批准号：
9892315
负责人：
Amy N Abell
金额：
$ 8.75万
依托单位：
UNIVERSITY OF MEMPHIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892315
关键词：
Acetylation Acetyltransferase Actins Active Sites Adherence Apical Back Biological Biological Assay Biological Markers Biological Process Breast Cancer Cell Cancer Control Cancer Patient Cause of Death Cell Surface Proteins Cells ChIP-seq Characteristics Chromatin Remodeling Factor Cytoskeleton Data Deacetylase Deacetylation Decidual Cell Reactions Defect Development Disease Drug Targeting Epigenetic Process Epithelial Epithelial Cells Event Fibrosis GALNT3 gene Gene Expression Gene Expression Profile Gene Expression Regulation Genes Goals HDAC6 gene Histone Acetylation Histone H2A Histone H2B Human In Vitro Individual Inflammation Injections Kidney Liver Lung Lysine Malignant Neoplasms Mediating Mesenchymal Molecular Morphology Mus Mutation Neoplasm Metastasis Overlapping Genes Pathologic Pathology Phenotype Phosphotransferases Physiological Processes Process Property Proteins Publishing Regulation Resistance Role Signal Pathway Signal Transduction Stem cells System Tissues Work base blastocyst cancer cell cell motility chromatin remodeling conventional therapy epigenetic regulation epithelial to mesenchymal transition human disease in vivo in vivo Model inhibitor/antagonist innovation knock-down malignant breast neoplasm new therapeutic target novel novel strategies overexpression prevent programs promoter small hairpin RNA stemness targeted treatment therapy resistant tissue regeneration transcription factor transcriptome sequencing trophoblast

项目摘要

PROJECT SUMMARY Epithelial to mesenchymal transition (EMT) is a developmental program in which non-motile epithelial cells with tight cell-cell adherence convert into individual, motile mesenchymal cells. Importantly, EMT is reversible through a mesenchymal to epithelial transition (MET) converting mesenchymal cells back to an epithelial state. The EMT program is essential for normal processes during development and for tissue regeneration. EMT is reactivated in human diseases including tissue fibrosis in the kidney, liver, and lung and in cancer metastasis, making EMT a key target for drug therapy. Targeted mutation of the active site lysine of the kinase MAP3K4 in the mouse (KI4) results in severe developmental defects due to disrupted EMT. Epithelial trophoblast stem (TS) cells from kinase-inactive MAP3K4 (KI4) mice (TSKI4 cells) are uniquely paused in the intermediate stages of EMT, expressing both epithelial and mesenchymal characteristics while maintaining stemness. Induction of EMT in TSKI4 cells is due in part to the loss of MAP3K4/CBP mediated acetylation of histone H2B on the promoters of genes controlling the epithelial phenotype. We have recently discovered that loss of MAP3K4 activity increases the expression and activity of another chromatin remodeler, HDAC6. The goal of this project is to define the molecular network regulated by MAP3K4 controlling EMT. This network includes signaling pathways leading to the epigenetic regulation of genes important for EMT. Our approach is based on both our published work and new findings showing that MAP3K4 coordinates EMT by activating CBP and inhibiting HDAC6 on the promoters of genes important for EMT. We predict that genes in this MAP3K4 controlled network are critical to EMT-related pathologies. Our rationale is based on our findings of overlapping gene expression signatures between our TSKI4 stem cells and claudin low breast cancer cells that both display characteristics of stemness and EMT. Cancers with these characteristics frequently are both metastatic and display resistance to therapy. Protein networks that regulate the EMT transition represent potential targets for therapy with the rationale that reversal of EMT would restore sensitivity towards therapy. Our preliminary work using this innovative system has successfully identified new genes in breast cancer that control EMT/MET. Aim1 uses RNA-seq and ChIP-seq to identify a MAP3K4/CBP/HDAC6/H2BK5Ac dependent network that controls EMT. Aim 2 is a mechanistic study of the role of MAP3K4 and HDAC6 in EMT and the impact on the KI4 cellular and organismal phenotypes. The third aim targets GALNT3, a MAP3K4/CBP/HDAC6/H2BK5Ac co- regulated gene, defining the mechanisms by which GALNT3 controls EMT. Together, the three aims of this proposal will define the signaling mechanisms by which MAP3K4 coordinates the cellular phenotype through the co-regulation of the chromatin modifiers CBP and HDAC6. Further, this proposal will identify and characterize novel genes regulating epithelial/mesenchymal states, leading to the discovery of new biomarkers and drug targets for the identification and treatment of EMT related pathologies like fibrosis and metastasis.

项目概要上皮到间质转化（EMT）是一种发育程序，其中非运动上皮细胞具有紧密的细胞-细胞粘附转化为个体、能动的间充质细胞。重要的是，EMT 是可逆的通过间充质到上皮细胞的转变（MET）将间充质细胞转变回上皮状态。 EMT 计划对于发育过程中的正常过程和组织再生至关重要。急救人员是在人类疾病中重新激活，包括肾、肝、肺组织纤维化以及癌症转移，使 EMT 成为药物治疗的关键目标。激酶 MAP3K4 活性位点赖氨酸的靶向突变小鼠 (KI4) 由于 EMT 中断而导致严重的发育缺陷。上皮滋养层干来自激酶失活 MAP3K4 (KI4) 小鼠的 (TS) 细胞（TSKI4 细胞）在中间阶段独特地暂停 EMT，表达上皮和间质特征，同时保持干性。感应 TSKI4 细胞中的 EMT 部分归因于 MAP3K4/CBP 介导的组蛋白 H2B 乙酰化的丧失控制上皮表型的基因启动子。我们最近发现 MAP3K4 的丢失活性增加另一种染色质重塑剂 HDAC6 的表达和活性。该项目的目标的目的是定义MAP3K4控制EMT所调控的分子网络。该网络包括信令导致对 EMT 重要基因进行表观遗传调控的途径。我们的方法基于我们的已发表的工作和新发现表明 MAP3K4 通过激活 CBP 和抑制来协调 EMT HDAC6 位于对 EMT 重要的基因启动子上。我们预测该 MAP3K4 中的基因控制网络对于 EMT 相关病理至关重要。我们的理由基于我们对重叠基因的发现我们的 TSKI4 干细胞和 Claudin Low 乳腺癌细胞之间的表达特征干性和 EMT 的特征。具有这些特征的癌症通常是转移性的和显示出对治疗的抵抗力。调节 EMT 转变的蛋白质网络代表了潜在的目标治疗的基本原理是逆转 EMT 将恢复对治疗的敏感性。我们的前期工作使用这一创新系统已成功鉴定出乳腺癌中控制 EMT/MET 的新基因。 Aim1 使用 RNA-seq 和 ChIP-seq 来识别 MAP3K4/CBP/HDAC6/H2BK5Ac 依赖网络控制 EMT。目标 2 是关于 MAP3K4 和 HDAC6 在 EMT 中的作用及其对 KI4 细胞和有机体表型。第三个目标是 GALNT3，一种 MAP3K4/CBP/HDAC6/H2BK5Ac 联合体调节基因，定义了 GALNT3 控制 EMT 的机制。综上所述，本次活动的三个目标该提案将定义 MAP3K4 通过以下方式协调细胞表型的信号传导机制：染色质修饰剂 CBP 和 HDAC6 的共同调节。此外，该提案将确定并表征调节上皮/间质状态的新基因，从而发现新的生物标志物以及用于识别和治疗 EMT 相关病理（如纤维化和转移）的药物靶点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GALNT3 Maintains the Epithelial State in Trophoblast Stem Cells.

GALNT3 维持滋养层干细胞的上皮状态。

DOI：
发表时间：
2019
期刊：
影响因子：
8.8
作者：
Raghu, Deepthi;Mobley, Robert J;Shendy, Noha A M;Perry, Charles H;Abell, Amy N
通讯作者：
Abell, Amy N

MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway.

MAP3K4 通过控制受体酪氨酸激酶 IGF1R/IR 和 Akt 信号通路促进胎儿和胎盘生长。

DOI：
发表时间：
2022-09
期刊：
影响因子：
0
作者：
Perry, Charles H;Mullins, Nathan A;Sweileh, Razan B A;Shendy, Noha A M;Roberto, Patrick A;Broadhurst, Amber L;Nelson, Hannah A;Miranda;Abell, Amy N
通讯作者：
Abell, Amy N

Controlling Epithelial to Mesenchymal Transition through Acetylation of Histone H2BK5.

通过组蛋白 H2BK5 的乙酰化控制上皮细胞向间质细胞的转变。

DOI：
发表时间：
2017-09
期刊：
影响因子：
0
作者：
Mobley, Robert J;Abell, Amy N
通讯作者：
Abell, Amy N

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.

MAP3K4、CBP 和 HDAC6 对 Rel 表达的协调调节控制着表型转换。

DOI：
发表时间：
2020
期刊：
影响因子：
5.9
作者：
Shendy, Noha Ahmed Mohammed;Raghu, Deepthi;Roy, Sujoy;Perry, Charles Hamilton;Safi, Adiba;Branco, Miguel Ramos;Homayouni, Ramin;Abell, Amy Noel
通讯作者：
Abell, Amy Noel

MAP3K4 kinase activity dependent control of mouse gonadal sex determination†.

MAP3K4 激酶活性依赖性控制小鼠性腺性别决定。