Enzymatic function of Hdac1 and cutaneous lipid metabolism

Histone deacetylase 1 (HDAC1) is a chromatin-modifying enzyme and a major epigenetic regulator that deacetylates histone and other proteins. HDAC1 plays a central role in various cellular signaling pathways and has been identified as a crucial factor in the regulation of cell growth, differentiation and organ development in mammals. Previous studies have also demonstrated a connection between protein acetylation and lipid metabolism. HDAC inhibitors are promising drugs that are currently being tested in clinical trials for the treatment of cancer and immunological or neurological disorders. By stabilizing multienzyme complexes, HDAC1 not only exhibits deacetylase activity but also has a non-enzymatic scaffolding ability. To analyze both functions, we developed new transgenic mouse lines that enables to study the catalytic and non-catalytic function of HDAC1. This allows the targeted expression of catalytically inactive HDAC1 (H141A) in keratinocytes and sebaceous glands of the skin instead of endogenous functional HDAC1. Preliminary data from analysis of these mice indicate that genetic inactivation of HDAC1 leads to pathological changes in the skin, including skin inflammation and enlarged sebaceous glands with deregulation of lipid-associated genes. In this project, we will investigate a nearly unexplored proposed role of HDAC1: the regulation of lipid metabolism in the skin. We use a combination of molecular biological, immunological and biochemical methods such as single-cell RNA sequencing and lipidomics. Since some skin lesions in the mice resemble the features of acne, we are also investigating the role of dynamic histone deacetylation in the development of acne vulgaris using tissue samples from affected patients. Our study aims to help clarify whether deregulated HDAC activity can lead to abnormal sebaceous homeostasis and changes in lipid metabolism. Additionally, we aim to create the scientific basis for clinical studies on the use of epigenetic drugs to treat acne vulgaris.