PXD050547-2

PXD050547 is an original dataset announced via ProteomeXchange.

Title	Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki Syndrome
Description	Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. Our data reveals that lysine methyltransferase epigenetic regulation is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:47:03.208.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD050547
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Mark Graham
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-11 21:38:16	ID requested
1	2024-06-23 01:45:15	announced
⏵ 2	2024-10-22 06:47:05	announced	2024-10-22: Updated project metadata.

10.6019/PXD050547;

10.1016/j.ebiom.2024.105156;

Tsang E, Han VX, Flutter C, Alshammery S, Keating BA, Williams T, Gloss BS, Graham ME, Aryamanesh N, Pang I, Wong M, Winlaw D, Cardamone M, Mohammad S, Gold W, Patel S, Dale RC, Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome. EBioMedicine, 104():105156(2024) [pubmed]

submitter keyword: neurodevelopment, TMTpro, butyrate, hydrophilic interaction liquid chromatography, single-cell RNA sequencing, lysine methyltransferase,Epigenetic, tandem mass tag

Russell Dale
contact affiliation	Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney
contact email	russell.dale@health.nsw.gov.au
lab head
Mark Graham
contact affiliation	Children's Medical Research Institute
contact email	mgraham@cmri.org.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050547
     1. Label: PRIDE project
     2. Name: Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki Syndrome