Transcriptional Co-Regulators in Epidermis

表皮中的转录协同调节因子

基本信息

批准号：
10555262
负责人：
Bogi Andersen
金额：
$ 43.98万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555262
关键词：
ATAC-seq Abbreviations Address Adhesions Appearance Atopic Dermatitis Biological Assay Cells Characteristics Chromatin Classification Color Data Deposition Development Differentiated Gene Enhancers Epidermis Epigenetic Process Funding Future Gene Expression Genes Genetic Transcription Genomics Glean Goals Grant Health Heterogeneity Human Impaired wound healing Impairment In Situ In Vitro Knowledge Left Literature Malignant Neoplasms Methods Modeling Morphology Mus Nature Pattern Pharmaceutical Preparations Play Population Principal Component Analysis Process Proliferating Property Psoriasis Publishing Regulation Resolution Role Signal Transduction Skin Skin Cancer Stratum Basale Surface System Technology Testing Transcription Coactivator Transcriptional Regulation Transposase Work blind cell motility cell type epithelial wound experimental study in vivo innovation insight intercellular communication keratinization keratinocyte mRNA Expression migration postmitotic progenitor programs promoter prototype self renewing cell single cell analysis single-cell RNA sequencing skin barrier skin disorder stem cells transcription factor transcriptome transcriptome sequencing wound wound healing

项目摘要

ABSTRACT Our long-term goal is to understand the transcriptional regulation of interfollicular epidermal (IFE) differentiation. The IFE is maintained by proliferating basal layer stem cells that self-renew, but also divide asymmetrically to generate postmitotic progeny deposited into the suprababasal compartment. As these progeny cells move toward the skin's surface they form successively the spinous, granular and cornified layers. The distinct morphology of each epidermal layer, combined with matching sharp boundaries in the expression of landmark genes, has established a stepwise differentiation model for the IFE. We have focused on the later IFE differentiation stages and their control by Grhl3, an evolutionarily conserved transcriptional regulator of epidermal barrier formation. Grhl3 also promotes keratinocyte migration where it activates a gene expression program distinct from that in differentiation. In this renewal application, we propose to employ emerging single cell approaches to define in vivo transcriptional regulation of IFE differentiation and collective keratinocyte migration- -at a scale and resolution not heretofore possible. In Aim 1, we will re-define IFE differentiation based on single cell RNA-seq (scRNA-seq) analysis. Our recent scRNA-seq experiments suggest that many gene batteries with distinct functions have expression patterns that cross different IFE layers, and that there is a large population of transition cells between the basal layer and the first spinous layer. Our hypothesis is that rather than a stepwise process, IFE differentiation is better understood as a continuous process where every cell in the IFE is at a distinct differentiation stage. We will use a new hybridization-based single cell method, to match our scRNA-seq data with landmarks in the IFE. We will also use ATAC-seq, to correlate chromatin accessibility with single cell mRNA expression. In Aim 2, we will understand how Grhl3 and other IFE regulators act in vivo. Unexpectedly, Grhl3 loss leads to an accumulation of an abnormal IFE cell population with progenitor characteristics. We will test the hypotheses that in addition to its well described role in activating terminal differentiation genes, Grhl3 suppresses the formation of this abnormal progenitor cell population. In Aim 3, we will define cellular heterogeneity in the migrating epithelial wound front. We will test the hypotheses that different regions of the migrating wound front contain groups of keratinocytes which can be classified based on their transcriptome and chromatin state; that there are cell signals within and between different keratinocyte populations of the wound front; that Grhl3 regulates adhesion properties of follower cells; and that cell heterogeneity, cell-cell signaling, and role of Grhl3 change as wound healing progresses. These experiments are significant and innovative because they will be the first to comprehensively characterize in an unbiased way the in vivo transcriptome heterogeneity of the IFE in differentiation and migration--relevant to many skin diseases. The premise is strong, based on extensive literature, published work on the role of Grhl3, and our recent scRNA-seq data.

抽象的我们的长期目标是了解裂纹表皮（IFE）分化的转录调节。通过增生自我更新的基底层干细胞来维持IFE，但也不对称地分裂产生沉积在上室室中的有丝分裂后后代。随着这些后代细胞的移动在皮肤的表面上，它们依次形成棘突，颗粒状和蜂蜜层。独特的每个表皮层的形态，与地标表达中匹配的锐角结合基因已建立了IFE的逐步分化模型。我们专注于以后的IFE 分化阶段及其控制，Grhl3是表皮的进化保守的转录调节剂屏障形成。 GRHL3还促进了角质形成细胞迁移，它激活了基因表达程序与分化不同。在此续订应用中，我们建议采用新兴的单元定义IFE分化和集体角质形成细胞迁移的体内转录调控的方法 - 以迄今为止不可能的规模和解决方案。在AIM 1中，我们将根据单个重新定义IFE分化细胞RNA-SEQ（SCRNA-SEQ）分析。我们最近的SCRNA-SEQ实验表明许多带有的基因电池不同的功能具有跨越不同层的表达模式，并且有大量人口基础层和第一个棘突之间的过渡细胞。我们的假设是，而不是逐步过程，IFE分化可以更好地理解为一个连续过程，其中IFE中的每个单元格在一个独特的分化阶段。我们将使用新的基于杂交的单细胞方法来匹配我们的scrna-seq 具有地标在IFE中的数据。我们还将使用ATAC-SEQ，将染色质的可及性与单个单元相关联 mRNA表达。在AIM 2中，我们将了解GRHL3和其他IFE监管机构如何在体内作用。不料， GRHL3损失导致具有祖细胞特征的IFE细胞种群的异常。我们将测试假设，除了其在激活末端分化基因中的作用外，GRHL3 抑制这种异常祖细胞群的形成。在AIM 3中，我们将定义细胞迁移的上皮伤口前部的异质性。我们将测试假设的假设迁移的伤口前部包含一组角质形成细胞，可以根据其转录组和染色质状态；伤口的不同角质形成细胞种群内和之间存在细胞信号正面; GRHL3调节了追随者细胞的粘附特性；细胞异质性，细胞 - 细胞信号传导，随着伤口愈合的进展，GRHL3的作用变化。这些实验是重要的和创新的因为它们将是第一个以公正的方式全面表征的体内转录组的人 IFE在分化和迁移方面的异质性与许多皮肤疾病相关。前提很强，基于广泛的文献，发表了有关GRHL3的作用的工作，以及我们最近的SCRNA-Seq数据。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clock genes, hair growth and aging.

DOI：
10.18632/aging.100130
发表时间：
2010-03-31
期刊：
Aging
影响因子：
0
作者：
Geyfman M;Andersen B
通讯作者：
Andersen B

Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells.

LIM 结构域的辅助因子 (Clims/Ldb/Nli) 调节角膜稳态和毛囊干细胞的维持。

DOI：
10.1016/j.ydbio.2007.09.052
发表时间：
2007
期刊：
Developmental biology
影响因子：
2.7
作者：
Xu,Xiaoman;Mannik,Jaana;Kudryavtseva,Elena;Lin,KevinK;Flanagan,LisaA;Spencer,Joel;Soto,Amelia;Wang,Ning;Lu,Zhongxian;Yu,Zhengquan;Monuki,EdwinS;Andersen,Bogi
通讯作者：
Andersen,Bogi

The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget's disease.

Msi1-mTOR 通路驱动乳房和乳房外佩吉特病的发病机制

DOI：
10.1038/s41422-020-0334-5
发表时间：
2020-10
期刊：
Cell research
影响因子：
44.1
作者：
Song Y;Guerrero-Juarez CF;Chen Z;Tang Y;Ma X;Lv C;Bi X;Deng M;Bu L;Tian Y;Liu R;Zhao R;Xu J;Sheng X;Du S;Liu Y;Zhu Y;Shan SJ;Chen HD;Zhao Y;Zhou G;Shuai J;Ren F;Xue L;Ying Z;Dai X;Lengner CJ;Andersen B;Plikus MV;Nie Q;Yu Z
通讯作者：
Yu Z

Circadian clock genes contribute to the regulation of hair follicle cycling.

DOI：
10.1371/journal.pgen.1000573
发表时间：
2009-07
期刊：
PLoS genetics
影响因子：
4.5
作者：
Lin KK;Kumar V;Geyfman M;Chudova D;Ihler AT;Smyth P;Paus R;Takahashi JS;Andersen B
通讯作者：
Andersen B

Inference of Intercellular Communications and Multilayer Gene-Regulations of Epithelial-Mesenchymal Transition From Single-Cell Transcriptomic Data.