Biology subjects

Lamartine, J.

Publications and source records attributed to Lamartine, J..

3 recordsLinked to original sources

bioRxiv2026

HDAC4/5 regulate epidermal barrier function by modulating the epigenetic landscape of human keratinocytes

Keratinocyte proliferation and differentiation are essential to produce the stratified structure of the epidermis and maintain its barrier function. These processes are regulated by complex mechanisms including epigenetic regulation. In this study, we evaluated the role of HDAC4/5, two class IIa histone deacetylases, in the epigenetic regulation of proliferative and differentiated human keratinocytes using dedicated 2D and 3D in vitro models. Our findings demonstrate that chemical inhibition or shRNA-mediated knock-down of HDAC4 impair keratinocyte proliferation notably through increased H3K27 acetylation and subsequent transcriptional activation of the cell cycle inhibitor gene BTG2. Interestingly, HDAC4/5 inhibition alters H3K27 acetylation landscape in proliferating keratinocytes, whereas the epigenetic identity of differentiated keratinocytes is much less affected. Inhibiting HDAC4/5 in 3D epidermis models resulted in reduced epidermal thickness and impaired barrier function linked to alteration in the lipid composition of the stratum corneum. Furthermore, analysis of several well-established skin aging markers revealed that reconstructed human epidermis treated with the HDAC4/5 inhibitor exhibit molecular and functional characteristics consistent with an aged-epidermis. Collectively, our results demonstrate that HDAC4/5 are essential for maintaining epidermal homeostasis and pave the way for the development of innovative models of skin aging based on the modulation of histone acetylation.

cell biology↗

bioRxiv2026

NFATc2 potentiates DNA double-strand breaks repair by interaction with Ku80 in radiotherapy patients

A fraction of patients treated with radiotherapy are known to be more sensitive to ionizing radiations. Skin fibroblasts from such radiosensitive individuals exhibit a higher cellular toxicity after irradiation and a delay in DNA repair. Deciphering the molecular mechanisms underlying these cellular defects is thus of major importance. We previously observed that the transcription factor NFATc2 is expressed at a reduced level in fibroblasts from radiosensitive patients. The present work aimed to elucidate the role of NFATc2 in the regulation of DNA repair, particularly the repair of radiation-induced double-strand breaks. We demonstrate an interaction of NFATc2 with the NHEJ repair protein Ku80 and observe that the NFATc2 RHD domain is necessary and sufficient for this interaction. Moreover, we show that NFATc2-Ku80 complexes are not colocalized to DNA double-strand breaks sites suggesting an involvement upstream of the DNA repair pathway. The silencing of NFATc2 impairs the NHEJ repair activities by delaying Ku70-Ku80 interaction in the early steps of this pathway. Finally, stable over-expression of NFATc2 in patients fibroblasts partially rescues their defective DNA repair phenotype, especially in the most radiosensitive cells. Altogether, our data reveal that NFATc2 is a regulator of DNA repair in skin fibroblasts and therefore a potential modulator of cellular radiosensitivity.

cell biology↗

bioRxiv2022

Chronological aging impacts abundance, function and microRNA content of extracellular vesicles produced by human epidermal keratinocytes

The disturbance of intercellular communication is one of the hallmarks of aging. The goal of this study is to clarify the impact of chronological aging on extracellular vesicles (EVs), a key mode of communication in mammalian tissues. We focused on epidermal keratinocytes, the main cells of the outer protective layer of the skin which is strongly impaired in the skin of elderly. EVs were purified from conditioned medium of primary keratinocytes isolated from infant or aged adult skin. A significant increase of the relative number of EVs released from aged keratinocytes was observed whereas their size distribution was not modified. By small RNA sequencing, we described a specific microRNA (miRNA) signature of aged EVs with an increase abundance of miR-30a, a key regulator of barrier function in human epidermis. EVs from aged keratinocytes were found to be able to reduce the proliferation of young keratinocytes, to impact their organogenesis properties in a reconstructed epidermis model and to slow down the early steps of skin wound healing in mice, three features observed in aged epidermis. This work reveals that intercellular communication mediated by EVs is modulated during aging process in keratinocytes and might be involved in the functional defects observed in aged skin.

cell biology↗