Chromatin regulation of epithelial stem cell function

上皮干细胞功能的染色质调节

• 批准号: 10582038
• 负责人: Adam David Gracz
• 金额: $ 16.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582038
• 关键词: Administrative Supplement; Adopted; Adult; Aging; Award; Biological Models; Cell Differentiation process; Cells; Chromatin; Development; Disease; Enhancers; Enzymes; Epithelial; Equilibrium; Exhibits; Foundations; Goals; Health; Homeostasis; Human; Infection; Inflammation; Informal Social Control; Injury; Instruction; Intestines; Life; Modeling; Natural regeneration; Parents; Property; Regenerative response; Regulation; Reporter; Research; Research Personnel; Running; Site; Tissues; Transgenes; adult stem cell; cell type; chromatin modification; epithelial stem cell; genomic locus; interest; intestinal epithelium; mouse model; novel; parent project; progenitor; programs; regeneration following injury; response; self-renewal; stem cell differentiation; stem cell function; stem cells; stemness; transcription factor; tumorigenesis

ABSTRACT Stemness is a functional cellular attribute defined by properties of multipotency (the ability to produce all differentiated cell types in a tissue) and self-renewal (the ability to produce new stem cells). In adult epithelial tissues, stemness can exist in: (1) dedicated stem cells occupying a defined niche, and (2) differentiated cells that exhibit plasticity to drive regeneration following injury. Stem cells must balance self-renewal with differentiation, and differentiated cells must balance lineage specific identity with plasticity to participate in regenerative responses. My lab is interested in understanding how chromatin modifications and their associated enzymes interact with site-specific transcription factors (TFs) to establish cell identities while simultaneously facilitating alternative cell fates. We focus on intestinal stem cells (ISCs), which drive the renewal of the intestinal epithelium approximately once a week throughout adult life, as a model system. Over the next five years, my research program will explore how TFs and chromatin modifying enzymes contribute to an exit from the stem cell state as ISC differentiate. Current models propose that rapid differentiation and plasticity in the intestinal epithelium is regulated by chromatin landscapes that are highly similar across all intestinal epithelial cell types, regardless of differentiation stage. Recent studies in my lab have challenged this model using a Sox9EGFP mouse model that allows us to isolate ISCs, progenitors, and differentiated cells with a single reporter transgene. We quantified changes in chromatin accessibility and 5-hydroxymethylcytosine and identified significant chromatin dynamics at genomic loci consistent with enhancers. Our analyses identified novel candidate TF-chromatin interactions and raise exciting questions about the importance of chromatin regulation in adult epithelial stem cells. Our future research will build on this progress to understand: (1) how stem cell- associated chromatin is decommissioned by TFs in differentiation, (2) how lineage-specific regulatory programs are “primed” in ISCs, and (3) how chromatin modifying enzymes bridge regulation of self-renewal and differentiation. The approach proposed here will establish a long-term research program, with broad potential to expand into studies of plasticity/de-differentiation, chromatin regulation of epithelial responses to environmental challenges, and development. Our goal is to pursue a basic mechanistic understanding of chromatin regulation in stemness that will have foundational relevance to human health and disease, including epithelial responses to inflammation, infection, injury, aging, and tumorigenesis.

抽象的 Stemness是由多稳定性的特性定义的功能性细胞属性（产生所有的能力 分化组织中的细胞类型）和自我更新（产生新干细胞的能力）。在成人上皮 组织，干性可以存在于：（1）专用的干细胞占据定义的小众细胞，（2）分化的细胞 暴露于受伤后驱动再生的可塑性。干细胞必须平衡自我更新 分化和分化细胞必须平衡谱系特定的身份与可塑性以参与 再生反应。我的实验室有兴趣了解染色质修饰及其相关的方式 酶与位点特异性转录因子（TF）相互作用以建立细胞身份，同时 促进替代细胞命运。我们专注于肠道干细胞（ISC），该干细胞驱动肠道的更新 在整个成人生活中，上皮大约是一个模型系统。在接下来的五年中，我 研究计划将探讨TFS和染色质修改酶如何促进退出 干细胞状态为ISC区分。当前模型提出的快速分化和可塑性 肠上皮受到所有肠上皮上高度相似的染色质景观的调节 细胞类型，无论分化阶段如何。我实验室的最新研究使用了 Sox9EGFP小鼠模型，使我们能够用一个报告者隔离ISC，祖细胞和分化细胞 转基因。我们量化了染色质可及性和5-羟基甲基胞嘧啶的变化，并确定了 基因组基因座的显着染色质动力学与增强子一致。我们的分析确定了小说 候选TF-染色质相互作用，并提出有关染色质调节重要性的令人兴奋的问题 在成年上皮干细胞中。我们未来的研究将以这一进展为基础：（1）干细胞如何 相关的染色质由TFS在分化中退役，（2）谱系特定的调节程序如何 在ISC中“启动”，（3）染色质如何修饰酶的自我更新和 分化。这里提出的方法将建立一项长期研究计划，并具有广泛的潜力 扩展到可塑性/脱不同的研究，对环境的上皮反应的染色质调节 挑战和发展。我们的目标是追求对染色质调节的基本机械理解 在与人类健康和疾病的基本相关性的茎中，包括上皮反应 炎症，感染，损伤，衰老和肿瘤发生。