565 Aberrant histone acetylation is linked to lysosomal and autophagic dysfunction in Cockayne syndrome (CS)

Abstract

Cockayne syndrome (CS) is a progeroid disease mainly caused by mutations in the CSB gene. As CS patients show UV hypersensitivity and cells lacking functional CSB protein are defective in transcription coupled DNA repair, CS is usually regarded as a DNA repair deficiency syndrome. Importantly, clinical hallmarks of CS suggest additional biological functions of CSB apart from DNA repair. In keeping with this assumption we have previously provided evidence for disturbed autophagy in CSB and that treatment of CSB deficient (CSBdef) mice with the HDAC inhibitor SAHA rescued their skin phenotype including inflammation, fibrosis and loss of subcutaneous fat. In the present study we link these two findings. We show that the development of the skin phenotype in CSBdef mice was associated with a blockade in autophagy due to lysosomal dysfunction as revealed by accumulation of autophagy- and lysosome-related proteins in their degenerated subcutis. Similar to mice, autophagic/lysosomal blockade was also present in CSBdef primary human fibroblasts and C. elegans. Moreover, CSBdef fibroblasts displayed reduced acetylation of H3K56 and H4K16, two histone lysine residues directly linked to regulation of autophagy. In line with that, we also detected high levels of HDAC1 and HDAC3 proteins in these cells and murine skin which are not only capable of deacetylating H3K56 and H4K16, respectively, but are also involved in regulation of autophagy suggesting involvement of an imbalanced acetylation in autophagic dysfunction and skin pathology. Accordingly, application of SAHA increased acetylation of both lysine residues in CSBdef fibroblasts and improved autophagic/lysosomal function in these cells, C. elegans and CSBdef mice. These results indicate a possible mechanistic link between epigenetic alterations, autophagy dysfunction and loss of subcutaneous fat in CS.