Does ectopic expression of germline genes during brain development contribute to autism?

Mutations in chromatin regulators have emerged as a major cause of autism spectrum disorder (ASD). Following the gene discoveries, many mouse models and human cells resembling these genetic lesions have been made and characterized. These chromatin-linked ASD models often display misregulation of genes with relevant brain functions, including synaptic plasticity. Most work has focused on such brain-associated genes to explain the cellular and behavioral phenotypes. An under-appreciated observation is that several ASD models display ectopic expression of germline genes, which should only be expressed in the testis or ovary¹. No work thus far has addressed the causal impact of mis-expressed genes on cellular and behavioral traits. This lack of knowledge limits our understanding of mechanisms underlying ASD. If germline gene expression causally impacts neurodevelopment, it would be an ideal drug target because such drugs would not directly interfere with any brain molecules.

The overarching goal of this proposal is to address the question: Does ectopic germline gene expression contribute to ASD? Shigeki Iwase’s focus is the X-linked lysine (K)-specific demethylase 5C (KDM5C), whose loss-of-function is responsible for a syndromic ASD characterized by intellectual disability, autistic features and aggressive behavior. As the name suggests, KDM5C reverses H3K4 methylation (H3K4me)², a hallmark of transcriptionally engaged chromatin, and the modification is conserved from yeast to humans.

Kdm5c-knockout (KO) mice recapitulate the key features of the above behaviors seen in individuals with the syndrome³. In addition, Iwase’s team’s unbiased survey of gene misregulation with RNA-seq revealed that the top altered genes were germline-specific genes, derepressed in Kdm5c-KO brain tissues⁴. Furthermore, Stra8 and Dazl, key genes for germline development, are present in Kdm5c-KO stem cells. These data indicate that Kdm5c deletion led to the soma-to-germline transformation to some extent.

The proposed study will test the hypothesis that germline gene expression bestows ‘germ-cellness’ to the mutant brain and contributes to neurodevelopmental alterations in Kdm5c-KO mice. The project addresses the impact of non-brain genes in ASD models for the first time. Transcriptional silencing of germline genes in somatic cells is proposed to be an essential step for multicellularity, which emerged 600 million years ago. Thus, the proposed study may reveal a deep evolutionary root of several ASD subtypes, that can be targeted in future therapeutics.

References

1. Bonefas K.M. and Iwase S. et al. FEBS J. 289, 2301–2317 (2022) PubMed
2. Iwase S. et al. Cell 128, 1077–1088 (2007) PubMed
3. Iwase Se. et al. Cell Rep. 14, 1000–1009 (2016) PubMed
4. Scandaglia M. et al. Cell Rep. 21, 47–59 (2017) PubMed