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Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Tejedor J.R.
  • Soriano-Sexto A.
  • Beccari L.
  • Castejón-Fernández N.
  • Sainz-Ledo L.
  • Alba-Linares J.J.
  • Urdinguio R.G.
  • Ugarte M.
  • Fernández A.F.
  • Rodríguez-Pombo P.
  • Fraga M.F.
  • Pérez B.

Grupos

Abstract

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the DBT promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of DBT promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases. © 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Datos de la publicación

ISSN/ISSNe:
0141-8955, 1573-2665

JOURNAL OF INHERITED METABOLIC DISEASE  WILEY

Tipo:
Article
Páginas:
-
PubMed:
39659154
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
1,296 SCImago ℠
Cuartil:
Q1 SCImago ℠

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Keywords

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); CCAAT-Enhancer-Binding Protein-beta; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Fibroblasts; Genomics; Humans; Male; Maple Syrup Urine Disease; Multiomics; Myeloid Ecotropic Viral Integration Site 1 Protein; Precision Medicine; Promoter Regions, Genetic; 2 oxoisovalerate dehydrogenase (lipoamide); adenine; cytosine; guanine; homeobox protein Meis1; thymine; transcription factor; transcription factor AP 1; transcription factor CEBPB; unclassified drug; 2 oxoisovalerate dehydrogenase (lipoamide); CCAAT enhancer binding protein beta; CEBPB protein, human; homeobox protein Meis1; Article; assay; BCKDH gene; cell cycle checkpoint; circular chromatin conformation capture assay; cohort analysis; controlled study; data integration; DBT gene; DNA methylation; epigenetic repression; epigenetics; fibroblast; gene cluster; gene interaction; genetic variability; genomics; Hox gene; human; human cell; human tissue; inheritance; maple

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