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Transcriptional and methylation profiling of adult skin keratinocytes upon aging

衰老时成人皮肤角质形成细胞的转录和甲基化谱

基本信息

批准号：
2125603
负责人：
金额：
--
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2125603
关键词：
Transcriptional methylation profiling adult skin

项目摘要

Currently, in-vivo epigenetic data has highlighted a plethora of methylation changes that consistently occur in the human epidermis with age (e.g. Vandiver et al, Genome Biol. 2015). These changes, however, are yet to be apportioned to either cellular ageing (e.g. free radical-induced DNA damage) or tissue structure/topology changes with age. We first plan to identify how the flattening of the epidermis with age impacts DNA methylation in keratinocytes. By seeding young keratinocyte stem cells on a young and old epidermal equivalent, we will be able to determine the effect of a flattened epidermis on its histopathology (e.g. keratinocyte differentiation rate), and the degree to which it drives epigenetic changes identified in in-vivo skin studies. Indeed, although methylation changes can take time to manifest themselves, there are large methylation changes that associate with cellular differentiation, a key process influenced by epidermal topology. Next, we will seed old keratinocyte stem cells onto identical epidermal equivalents and determine to what degree older stem cells compared to younger stem cells further recapitulate in-vivo epigenetic differences in the epidermis with age. Once differentially methylated DNA sites are linked to topological or cellular ageing, bioinformatics techniques can be applied to identify mechanisms driving the methylation changes, such as identifying transcription factors that bind to the DNA methylation sites, and correlations between methylation and mRNA levels in publically available datasets. We will define a bioinformatic workflow for classifying and then identifying cellular and topological driven methylation changes in other epigenetic datasets. In addition, we will confirm the impact of the methylation changes using histopathological analyses of the epidermal equivalents such as confirming changes to protein levels and function.

目前，体内表观遗传学数据已经强调了随着年龄的增长在人表皮中持续发生的大量甲基化变化（例如Vandiver等人，Genome Biol.2015）。然而，这些变化尚未被分配到细胞老化（例如自由基诱导的DNA损伤）或组织结构/拓扑结构随年龄的变化。我们首先计划确定随着年龄的增长表皮的扁平化如何影响角质形成细胞中的DNA甲基化。通过将年轻的角质形成细胞干细胞接种在年轻和年老的表皮等同物上，我们将能够确定扁平表皮对其组织病理学的影响（例如角质形成细胞分化率），以及它驱动体内皮肤研究中鉴定的表观遗传变化的程度。事实上，尽管甲基化变化可能需要时间才能显现出来，但存在与细胞分化相关的大的甲基化变化，这是受表皮拓扑结构影响的关键过程。接下来，我们将把老的角质形成细胞干细胞接种到相同的表皮等同物上，并确定与年轻干细胞相比，老的干细胞在多大程度上进一步概括了表皮中随年龄增长的体内表观遗传差异。一旦差异甲基化的DNA位点与拓扑或细胞衰老相关联，生物信息学技术就可以应用于识别驱动甲基化变化的机制，例如识别与DNA甲基化位点结合的转录因子，以及在可获得的数据集中甲基化和mRNA水平之间的相关性。我们将定义一个生物信息学工作流程，用于分类，然后识别其他表观遗传数据集中细胞和拓扑驱动的甲基化变化。此外，我们将使用表皮等同物的组织病理学分析来确认甲基化变化的影响，例如确认蛋白质水平和功能的变化。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamic regulation of human epidermal differentiation by adhesive and mechanical forces.

粘附力和机械力对人类表皮分化的动态调节。

DOI：
10.1016/bs.ctdb.2022.03.004
发表时间：
2022
期刊：
Current topics in developmental biology
影响因子：
0
作者：
Zijl S
通讯作者：
Zijl S

Plating human iPSC lines on micropatterned substrates reveals role for ITGB1 nsSNV in endoderm formation.

DOI：
10.1016/j.stemcr.2021.09.017
发表时间：
2021-11-09
期刊：
Stem cell reports
影响因子：
5.9
作者：
Vickers A;Tewary M;Laddach A;Poletti M;Salameti V;Fraternali F;Danovi D;Watt FM
通讯作者：
Watt FM

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair.