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Series GSE102250 Query DataSets for GSE102250
Status Public on Aug 06, 2018
Title De novo mutations of MSL3 cause a novel X-linked syndrome due to impaired histone H4 lysine 16 acetylation
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Epigenetic regulation by histone acetylation plays a key role in cellular homeostasis and its misregulation is associated with human disease. The Male Specific Lethal (MSL) complex associated MOF/KAT8 histone acetyl-transferase is responsible for bulk Histone 4 Lysine 16 acetylation (H4K16ac) in flies and mammals. H4K16ac is a peculiar case amongst the many histone tail modifications in directly affecting higher order chromatin compaction. 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 both male and female individuals. Common clinical features of the syndrome include a global delay in developmental milestones and speech, a progressive gait disturbance and recognizable dysmorphism. Using skin biopsies and 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 globally impacting H4K16ac levels in vivo. Transcriptome analysis from patient cells showed misregulation of cellular pathways involved in morphogenesis, cellular shape and cell migration. Using RNAi and MSL3 reintroduction experiments, we phenocopy acute responses occurring on H4K16ac-sensitive MSL target genes, supporting that this syndrome is caused by the loss of MSL3. Finally, we use HDAC inhibitors to rebalance acetylation levels and are able to alleviate both molecular and cellular phenotypes of MSL3 patients cells. Taken together, we characterize a novel syndrome, 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.
Overall design RNA sequencing of human primary fibroblasts from control and patients with various truncations of MSL3 with and without panobinostat treatment
Contributor(s) Semplicio G, Basilicata MF, Akhtar A
Citation(s) 30224647
Submission date Aug 04, 2017
Last update date Jan 28, 2019
Contact name Asifa Akhtar
Organization name Max Planck Institute of Immunobiology and Epigenetics
Department Chromatin Regulation
Lab Akhtar Lab
Street address Stuebeweg 51
City Freiburg
ZIP/Postal code 79108
Country Germany
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (16)
GSM3068352 control_dmso rep1
GSM3068353 control_dmso rep2
GSM3068354 control_pano rep1
BioProject PRJNA397133
SRA SRP114824

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Supplementary file Size Download File type/resource
GSE102250_RAW.tar 383.4 Mb (http)(custom) TAR (of BW)
GSE102250_counts.txt.gz 462.7 Kb (ftp)(http) TXT
GSE102250_dmso_pano_counts.tsv.gz 842.8 Kb (ftp)(http) TSV
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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