Coexpression patterns define epigenetic regulators associated with neurological dysfunction.

Area of Science:

• Genetics
• Epigenetics
• Neuroscience

Background:

• Coding variants in epigenetic regulators (EM) are linked to neurological dysfunction and cancer.
• A comprehensive analysis of disease candidates within the human EM is lacking.
• It is unclear what distinguishes variation-intolerant from variation-tolerant EM genes or those linked to neurological dysfunction versus cancer.

Purpose of the Study:

• To define and analyze the human epigenetic machinery (EM) gene set.
• To identify novel EM disease candidates.
• To investigate features distinguishing variation intolerance and disease associations within EM genes.

Main Methods:

• Defined 295 human EM genes (writers, erasers, remodelers, readers).
• Analyzed gene variation intolerance, function (single vs. dual), and tissue-specific coexpression.
• Investigated associations with neurological dysfunction and cancer, and genetic importance of regulatory regions.

Main Results:

• Identified 102 novel EM disease candidates; most EM genes are highly intolerant to loss-of-function variation.
• Variation intolerance is driven by protein domains encoding epigenetic function, suggesting disease arises from perturbed chromatin.
• A subset of highly variation-intolerant, dual-function EM genes is enriched for neurological dysfunction association, linked to tissue coexpression and regulatory region importance.

Conclusions:

• Prioritized novel EM disease candidates, particularly for neurological disorders.
• Epigenetic machinery genes are critical for neurological homeostasis, with variation intolerance linked to function and tissue coexpression.
• Perturbed chromatin states due to variation in EM genes likely cause disease.