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Weaver syndrome
Disease modelling in human brain organoids

Küster, Karolin | karolin.kuester@mailbox.tu-dresden.de
Center for Molecular and Cellular Bioengineering, Technische Universität Dresden
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Weaver syndrome is a rare developmental disorder characterized by an overgrowth of body and
head, abnormal brain structures as well as intellectual disability. It is caused by mutations of a
protein complex called Polycomb Repressive Complex 2 (PRC2). PRC2 plays an important role in
the epigenetic regulation of human development.
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Epigenetic mechanisms lead to changes in gene function that are heritable without changing the
DNA sequence. DNA is wrapped around proteins called histones. DNA and histone complexes to-
gether form chromatin. An epigenetic mechanism regulated by PRC2 is the modification of his-
tones by methylation. Histone methylation influences the structure of chromatin leading to gene
silencing and eventually alters gene activation and cell fate. Overall, epigenetic regulation leading
to gene silencing is an important process during embryonic development.

Epigenetic regulation, including Polycomb regulation, was shown to influence brain development,
thereby shaping brain size and structure. Up to now, little is known about the effect of Weaver
syndrome-associated mutations on human brain development.

To study Weaver syndrome in the context of human brain development, induced pluripotent stem
cell lines carrying disease-associated mutations were generated. Human brain organoids were
generated from these cell lines. Brain organoids represent a self-organizing, 3D in vitro model of
brain development. We can use these organoids to investigate abnormalities in brain development
associated with Weaver syndrome.

We could show that global levels of the PRC2-mediated methylation mark are reduced in Weaver
stem cell lines and organoids. This suggests that gene silencing might be reduced in this human
Weaver syndrome model. To analyze overgrowth phenotypes observed in Weaver syndrome pa-
tients, brain organoid size was assessed. The data revealed significant differences between Weaver
syndrome and control brain organoids.
Further analysis of this human disease model will allow us to study cellular and molecular changes
in Weaver syndrome brain development and to better understand the involvement of epigenetics
in developmental diseases.

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