Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation

Elife. 2021 Aug 31:10:e65884. doi: 10.7554/eLife.65884.


Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

Keywords: IgA deficiency; Mendelian; chromatin; computational biology; computational methods; epigenetics; genetics; genomics; histone machinery; mouse; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Animals
  • Chromatin / genetics
  • Disease Models, Animal
  • Epigenesis, Genetic / genetics*
  • Face / abnormalities*
  • Female
  • Genetic Techniques
  • Genetic Variation / genetics*
  • Hematologic Diseases / genetics*
  • Hematologic Diseases / metabolism
  • Mice
  • Phenotype
  • Rubinstein-Taybi Syndrome / genetics*
  • Rubinstein-Taybi Syndrome / metabolism
  • Transcriptome / genetics*
  • Vestibular Diseases / genetics*
  • Vestibular Diseases / metabolism


  • Chromatin

Supplementary concepts

  • Kabuki syndrome

Associated data

  • GEO/GSE162181