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In individuals with Williams syndrome, dysregulation of methylation in non-coding regions of neuronal and oligodendrocyte DNA is associated with pathology and cortical development

Molecular Psychiatry volume 28, pages 1112–1127 (2023)Cite this article

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Abstract

Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer–promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type–specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.

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Fig. 1: 7q11.23 deletion promotes genome-wide aberrations in the human frontal cortex DNA methylation landscape.
Fig. 2: The assocciation between 7q11.23 deletion, aberrant DNA methylation and TF binding.
Fig. 3: Consulting the human brain interactome to map aberrant methylation of regulatory elements and their target genes.
Fig. 4: Abnormal methylation patterns in individuals with WS are associated with genes involved in myelination and glia differentiation.
Fig. 5: Cell type–specific methylation analysis reveals aberrant patterns in individuals with WS, predominantly in active neuron enhancers.
Fig. 6: A comparison of methylated risk loci between brain and blood samples from individuals with WS identified three major gene clusters.

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Acknowledgements

The authors acknowledge the input from the members of the Barak and Marco laboratories on the manuscript and the study. Human tissue was obtained from the NIH NeuroBioBank at the University of Maryland. We thank the donors of the brain tissue and their families for their invaluable donations for the advancement of scientific understanding. This work is supported by grants from the Fritz Thyssen Stiftung (Ref. 10.19.1.011MN) and the Israeli Science Foundation (Number 2305/20).

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  1. These authors contributed equally: Asaf Marco, Boaz Barak.

Authors and Affiliations

  1. The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel

    Sari Schokoroy Trangle, Ela Bar & Boaz Barak

  2. Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel

    Tali Rosenberg, Hadar Parnas & Asaf Marco

  3. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel

    Gilad Levy & Boaz Barak

  4. The School of Neurobiology, Biochemistry & Biophysics, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel

    Ela Bar

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SST, AM, and BB designed the experiments and wrote the manuscript. SST, TR, HP, GL, EB, AM and BB collected, analyzed and interpreted the results.

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Trangle, S.S., Rosenberg, T., Parnas, H. et al. In individuals with Williams syndrome, dysregulation of methylation in non-coding regions of neuronal and oligodendrocyte DNA is associated with pathology and cortical development. Mol Psychiatry 28, 1112–1127 (2023). https://doi.org/10.1038/s41380-022-01921-z

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