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Genomics and Radiobiology of Keratinopoiesis - LGRK

Published on 18 June 2019




Michèle MARTIN
Principal investigator
Phone : +33 (0)1 60 87 34 91
miche​le​.martin@cea.fr

Genopole
2 avenue Gaston Crémieux
91000 EVRY cedex
France

The team “Genomics and Radiobiology of Keratinopoiesis” dissects the role of the TGF-b1 network in stemness and self-renewal of human keratinocyte stem cells, as well as the mechanisms used by these cells to maintain long-term genetic stability, notably after exposure to ionizing radiation. 


​Research project

Epidermis is the multilayered epithelium that covers the human skin. This tissue is in perpetual renewal, a process named keratinopoiesis, which is maintained through stem cells and their ability to self-renew. Although the suitability of epidermis stem cells for regenerative medicine have been obtained more than three decades ago, allowing skin autologous grafts in cases of deep second and third degree burns, significant challenges remain, among which a thorough comprehension of the cellular and molecular factors involved in the control of stem cell engraftment. 

The team explores a network of transcription factors related to the TGFb1 pathway at a fundamental level, to dissect their roles in stem cell immaturity and self-renewal, ,and with the aim to contribute to future connections between the knowledge of the molecular mechanisms that ensure keratinopoiesis and the medical area of cutaneous cell therapy.

Due to its anatomical localization and high turnover, epidermis is a major target for carcinogens, and skin carcinoma is one of the most frequent human cancers. Ionizing radiation (IR) can induce carcinoma in skin, but the respective roles of keratinocyte stem cells and their progeny in the carcinogenic process is still unclear. Moreover, the issue of threshold dose is still open for skin cancer after very low doses, as it was recently lowered to 0.6 Gy from the last data of last Japanese cohort survey. The team investigates keratinocyte radiosensitivity in normal epidermis precursor cells, notably in a cohort representative of the general French population, set up to address individual radiosensitivity. Radiosensitivity is also investigated in cells mutated for the PTCH1 gene, coding for the Sonic hedgehog receptor and responsible for the Gorlin syndrome. Target cells, target genes and the mechanisms of cell transformation after medium and low radiation doses are in the frame of these studies.

The team is involved in French research networks (ANR, ANSES, EDF, OSEO), as well as European networks (RISK-IR FP7), with academic and industrial partners. 

Methods and expertise
  • Biology of keratinocytes and fibroblasts from human skin, investigations at a clonal level.
  • Functional genomics, shRNA, lentiviral infections, gene profiling through DNA arrays , methylation arrays, RNA-Seq, long non-coding RNAs.
  • Human skin reconstruction in vitro, in vivo xenografts in nude mice, histology, immuno-histochemistry.
  • Radiobiology of skin cells and precursor cells, gamma rays, X-rays.
  • Radiosensitivity assays, nuclear foci, genomic and epigenomic instability, methylation.