By Clarice Tse
Psychiatric and developmental disorders are often long-lasting if not life-long diseases that impact not only the sufferers but also their friends and families. Unlike infectious diseases or chronic diseases that may be cured, mental and developmental disorders are the hardest tackle, as the cause and origin of these diseases depends on multiple factors. Moreover, currently, these disorders can only be alleviated but not cured. Therefore, it is crucial to find the origin and factors leading to the disease in order to help aid the discovery of more strategies to tackle and cure these disorders.
After years of research, genetics has always been speculated to contribute to the susceptibility to these diseases, as it was shown that some families with a history of mental/ developmental disorders have a higher risk of acquiring these diseases. Recently, Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD) was found to have overlapped biological pathways, genetic risk factors and phenotypic features, despite being classified as two different psychiatric disorders. Genome-wide studies have suggested that rare copy number variations (CNVs) and single nucleotide variations may possibly elucidate the pathophysiology of these disorders.
It was found that dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairment, which has been implicated in SCDs and ASDs. Copy number variations (CNVs) are variations where sections of the genome are repeated and the number of repeats in the genome varies between individuals. Recent studies of CNV and studies on the exome shows that numerous genes involved in the post translational histone lysine methylation, such as genes encoding histone demethylases and histone methyltransferases that regulate histone 3 lysine 9 methylation are involved in the neurodevelopmental impairment observed in SCD and ASD patients. Moreover, studies using mice with mutated histone demethylase and histone methyltransferase revealed the regulatory role of methylation patterns at histone h3-lysine 9 and histone h3-lysine 36 on genes related to brain function like the release of serotonin and symptoms anxiety and depression (Walsh et al., 2017). Results of the studies showed also showed deficits in neural maturation synaptic dysfunction, and behavioral characteristics linked to SCZ and ASD.
Among them, Lysine Demthylase 4C, encoded by KDM4C, functions to demethylate H3K9me2/me3 and H3K36me2/me3 was suspected to play a role in the abnormal behavior exhibited in ASD patients. This is supported by the study of Kdm4c hypomorphic mutant (a mutation that causes the loss of function/ reduced function of a gene) mice which revealed them to have abnormal behaviours like hyperactivity, persistence, and learning and memory deficits. Previous studies also showed that KDM4C control intrinsic glial fibrillary acidic protein (GFAP) expression and astrocyte differentiation in neural progenitors and are selectively associated with the methylation patterns of H3K36. GFAP-positive astrocytes are increased in the brain of Kdm4c hypomorphic mutant mice, which have phenotypic features that resemble the characteristics of developmental disorders including ASD (Sudo et al., 2016). In addition, SCZ and ASD cases with KDMC copy number variations (CNVs) were reported. Therefore, scientists hypothesized that rare CNVs and SNVs in KDM4C may confer susceptibility to these disorders.
Scientists carried out a study to identify rare CNVs in an expanded sample set of patients with SCZ and ASD. Array comparative genomic hybridization (aCGH) was used to quickly scan through sample genomes for CNVs, it was performed on 2810 SCZ cases, 1182 ASD cases and 2482 controls. 9 cases of exonic CNVs of KDM4C duplications in SCZ and 3 cases in ASD were identified, but none were found in the controls. Among the detected CNV cases, 8 were of deletions. Two were of deletions in the exons encoding JmjC domain which plays a central role in histone lysine demthylation. In another case, it was the removal of the 5’-untranslated region and the putative promoter region of upstream of the transcription-start site. The rest were deletions in the first exon of different transcription variants.
However, there was a need to know whether there was a true association between the rare CNVs and SCZ and ASDs. Hence, association studies were conducted to understand whether the CNVs found in KDM4C that were identified in the sample set actually have significant association with the disorders. A significant association between KDM4C CNVs and SCZ (p = 0.003; OR = 16.9) and ASD (p = 0.04; OR = 14.2) was found. Further analysis found that there was a significant association with deletions in the SCZ cases but not for duplications. On the other hand, neither deletions nor duplications were significantly associated with ASD cases. This means that, the exonic deletions in KDM4C in patients actually shows a correlation/ association to the SCZ disorder. From this it could be predicted that such deletions lead to modifications of the Lysine Demthylatse 4C which causes it to be unable to perform its function of demthylating lysine 3 and 36 of histone 3. This affects the methylation patterning of these lysines, which in turn impairs neural development and maturation, or the normal function and processes of neurons of the brain.
Furthermore, LCLs (human lymphocytes transformed with Epstein−Barr virus) from patients with KDM4C CNVs were prepared for mRNA analysis and it was found that in a patient of KDM4C deletion, there was a decreased expression of the KDM4C mRNA, with elevated levels of H3K9me2 and H3K9me3 and H3K36me3, which suggests that the decreased KDM4C expression changed the lysine methylation patterns on histones (Kato et al., 2020).
However, the physiological functions of KDM4C in neural development is still a myth. Little is understood about the mechanism of KDM4C CNVS in increasing the risk of SCZ and ASDs, although studies have already established a significant association between them. Therefore, further research is needed to explore how KDM4C regulates histone lysine methylation in neural development and how these events contribute to neurogenesis, and the possible onset of developmental disorders. It is possible to use stem cells to induce glial cells and neural cells for analysis in the future.
Walsh, R., Shen, E., Bagot, R., Anselmo, A., Jiang, Y., Javidfar, B., Wojtkiewicz, G., Cloutier, J., Chen, J., Sadreyev, R., Nestler, E., Akbarian, S. and Hochedlinger, K., 2017. Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice. Nature Communications, 8(1).
Sudo, G., Kagawa, T., Kokubu, Y., Inazawa, J. and Taga, T., 2016. Increase in GFAP-positive astrocytes in histone demethylase GASC1/KDM4C/JMJD2C hypomorphic mutant mice. Genes to Cells, 21(3), pp.218-225.
Kato, H., Kushima, I., Mori, D., Yoshimi, A., Aleksic, B., Nawa, Y., Toyama, M., Furuta, S., Yu, Y., Ishizuka, K., Kimura, H., Arioka, Y., Tsujimura, K., Morikawa, M., Okada, T., Inada, T., Nakatochi, M., Shinjo, K., Kondo, Y., Kaibuchi, K., Funabiki, Y., Kimura, R., Suzuki, T., Yamakawa, K., Ikeda, M., Iwata, N., Takahashi, T., Suzuki, M., Okahisa, Y., Takaki, M., Egawa, J., Someya, T. and Ozaki, N., 2020. Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. Translational Psychiatry, 10(1).