The ATP-dependent chromatin remodeler BRG1 controls epidermal keratinocytes migration during human cutaneous wound healing

C. Kellett1, N. Botchkareva1, R. Bhogal2, and M. Fessing1
1University of Bradford, Bradford, UK, 2Unilever Global R&D Centre, Sharnbrook, UK

SWI/SNF ATP-dependent chromatin remodelling complexes alter nucleosome structure, positioning and chromatin compaction state resulting in target gene activation or repression. The SWI/SNF complexes contain either BRG1 or BRM as the core ATPase together with other common and variable subunits. BRG1 is required for epidermal terminal differentiation in both mice and human, and for hair follicle stem cell activation during mouse hair regeneration and cutaneous wound healing. However, the role of SWI/SNF complexes in human skin wound healing remains unknown.

Here, we demonstrate that genes encoding SWI/SNF complex subunits are expressed in human epidermis, and BRG1 is substantially upregulated in hyper-proliferating and migrating keratinocytes in healing cutaneous wounds. siRNA mediated BRG1 gene suppression leads to the substantial retardation of the wound closure  in the full thickness human excision wounded skin tissue culture model and in scratched human primary keratinocyte monolayers. Furthermore, we showed that the retardation in the keratinocyte migration with no changes in cellular proliferation or apoptosis. Micro-array based transcriptome analysis revealed that BRG1 is required for full induction of genes encoding several signaling molecules, transcription factors and structural proteins involved in changes in cellular adhesion and cytoskeletal organization, driving keratinocyte migration during skin wound healing, including the stress cytokeratins 16 and 17. 

In summary, our data uncovered an essential role of the BRG1 chromatin remodeler in the induction of the transcription programme driving keratinocyte migration during skin wound closure and re-epithelisation.