CHROMATIN IN SKIN

Deciphering the role of chromatin in epidermal stem cell biology

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 Obiettivo del progetto (Objective)

'The skin is a multi-layered epithelium consisting of interfollicular epidermis (IFE), hair follicles (HF), sebaceous glands (SG) and apocrine (sweat) glands. Continuous shedding of terminally differentiated keratinocytes necessitates constant regeneration to ensure tissue homeostasis. This depends on the epidermal stem cell compartment located on top of the basement membrane. Several of the signaling pathways involved in this process are known (e.g. Myc, Wnt, Rac1, Notch, and EGFR) and under investigation. Commonly, the end-point of signaling pathways is regulation of transcription. In the cell, transcription takes place in a chromatin context and requires modification of the histones. However, the role of these modifications in epidermal stem cell maintenance and differentiation remains poorly understood. The proposed work aims to provide novel insights into the function of chromatin in these processes. Human epidermal stem cells are easily obtained and retain their ability to terminally differentiate in vitro upon certain stimuli, as determined by involucrin expression. Making use of sh/siRNA mediated knock-down, factors involved in regulation of chromatin will be tested for their role in epidermal stem cell differentiation. Interestingly, recent work of the Watt laboratory showed that Myc-induced differentiation involves histone acetylation. A second of research will be aimed at identifying the gene-expression programs underlying lineage commitment. Recent advances have been made in the Watt laboratory to differentiate human sebocytes into either IFE or SG. This system will be subjected to gene expression profiling to uncover the determinants of commitment to either lineage. In addition, RNAi based screens for chromatin factors involved in this process will be initiated. Finally the role of the identified chromatin factors in the formation of epidermal benign and neoplastic anomalies will be investigated using established in vivo murine-based approaches'

Introduzione (Teaser)

An EU-funded project has made a major research breakthrough into how skin regenerates. Their findings have shed light on how the whole process manages to be so robust and resistant to error.

Descrizione progetto (Article)

Skin is a complete organ. It protects us from the ravages of invasion by pathogens, extreme temperature and water loss. Moreover, it feels, breathes, gets rid of waste, and grows. It must grow rapidly and constantly as there is constant shedding of the dead (terminally differentiated) skin cells at the surface.

Regeneration every 21 days depends on a layer of epidermal stem cells as yet undifferentiated into their final form. In order to bring about this transformation of stem cells, there are several signalling pathways that control and regulate the processes involved.

The 'Deciphering the role of chromatin in epidermal stem cell biology' (Chromatin in skin) team took human epidermal stem cells and stimulated them to develop in vitro. While the process was in full swing, the scientists used a technique called gene silencing by optimally introducing chromatin factors (nuclear material). When a gene is silenced, it does not do its job, which in itself identifies the role of that gene.

The project was very successful. The role of no less than 332 chromatin-related factors was determined and 5;000 data points analysed to determine which genes were being expressed and when. This led to the discovery of two functionally connected epigenetic self-renewal mechanisms that cause changes in skin renewal through means other than alteration of the DNA.

The significance of the research in areas like skin cancer is obvious. Mechanisms behind stem cell development will also help to explain the wonders of our intricate yet virtually foolproof maturation and regeneration systems.