Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice

Genome Res. 2024 Jun 25;34(5):696-710. doi: 10.1101/gr.278416.123.


Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically shows phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption-the root of the pathogenesis-is similar in the different disease-relevant cell types. This is possible in principle, because all these cell types are subject to effects from the same causative gene, which has the same kind of function (e.g., methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2 and find that the chromatin accessibility changes in neurons are mostly distinct from changes in B or T cells. This is not because the neuronal accessibility changes occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that regulatory elements disrupted in B/T cells do show chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we are able to identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators and suggest that blood-derived episignatures, although useful diagnostically, may not be well suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

Publication types

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

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Aging* / genetics
  • Animals
  • B-Lymphocytes / metabolism
  • Chromatin* / genetics
  • Chromatin* / metabolism
  • CpG Islands*
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Face* / abnormalities
  • Hematologic Diseases* / genetics
  • Hematologic Diseases* / metabolism
  • Mice
  • Neurons* / metabolism
  • T-Lymphocytes / metabolism
  • Vestibular Diseases* / genetics


  • Chromatin

Supplementary concepts

  • Kabuki syndrome