De novo mutations of MSL3 cause a novel X-linked syndrome due to impaired histone H4 lysine 16 acetylation

ABSTRACT: Epigenetic regulation by histone acetylation plays a key role in cellular homeostasis and its misregulation is associated with human disease. Histone 4 Lysine 16 acetylation (H4K16ac) serves a unique role amongst the many histone modifications as it directly affects chromatin structure1. The Male Specific Lethal (MSL) complex associated MOF/KAT8 histone acetyl transferase is responsible for bulk H4K16ac in flies and mammals. Yet, its importance during human development and a potential involvement in human pathologies remains largely unknown. Here, we uncover that pathogenic variants in MSL3, a component of the MSL complex, are causative for a new recognizable X-linked syndrome affecting Histone 4 Lysine 16 acetylation (H4K16ac) in both male and female individuals. Common clinical features of the syndrome include global developmental delay comprising profound speech delay, delayed ability to walk and craniofacial dysmorphism. Using patient-derived primary fibroblasts, we demonstrate that de novo variants or deletions of MSL3 affect the assembly and enzymatic activity of the MSL complex, hence impacting on global H4K16ac levels. Transcriptome analysis from patient cells showed misregulation of cellular pathways involved in serotonergic signaling, morphogenesis, axon guidance and cell structure. Finally, using HDAC inhibitor treatment, we can rescue expression of downregulated target genes, offering potential therapeutic avenues for MSL3-mutated patients. Taken together, we characterize a novel syndrome, named ILyADe (Impaired Lysine 16 acetylation associated disorder), which is caused by mutations of an epigenetic regulator, allowing us for the first time to unravel the crucial role of H4K16ac during human development. ILyaDe thus constitutes a new class of syndromes associated with misregulation of a single epigenetic modification caused by a genetic alteration.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Skin, Fibroblast

DISEASE(S): Global Developmental Delay

SUBMITTER: Witold Szymanski  

LAB HEAD: Dr. Gerhard Mittler

PROVIDER: PXD009317 | Pride | 2018-09-18

REPOSITORIES: Pride