The University of Michigan Medical School
Human Genetics Department
Ann Arbor, MI, 48108
Email: siwase@umich.edu
Phone: +1-734-647-8832
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Uncover Histone-based Mechanisms underlying Neurodevelopmental Disorders
Unlike the synapses, the nucleus is a less well studied compartment within neurons. Within the nucleus, the heritable information, the DNA, is wrapped around four small proteins known as “histones” (H2A, H2B, H3, and H4). Recent advances in human genetics have made it increasingly clear that these histones can be a major cause of intellectual disabilities (IDs) and Autism Spectrum Disorders (ASDs) if their regulatory mechanisms are disrupted by genetic mutations. However, it is largely unknown how such mutations can lead to abnormal brain development and function. A principal aim of our research is to elucidate the histone-related mechanisms underlying IDs and ASDs.
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Neurodevelopmental Disorders
include Autism Spectrum disorders (ASD) and Schizophrenia, which afflict a substantial human population. Neurodevelopmental disorders therefore represent a major medical issue. Affected individuals suffer from impaired cognitive and adaptive behaviors. Cognitive deficits involve sub-average abilities in reasoning and analytical thinking. People with such disorders also have problems in managing emotions such as fear and anxiety. At a cellular level, abnormalities in neuronal connectivity including dendritic/axonal morphology and synaptic development/function have been implicated in the pathology of neurodevelopmental disorders.
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Histone Modifications
include acetylation, phosphorylation, methylation, and other chemical marks deposited on the histone proteins. The primary information encoded in DNA is the amino acid sequences of proteins, which are the building blocks of cells. Compared to the beautiful simplicity of this “genetic code”, histone modifications seem to be far more complex. For example, some of these modifications play key roles in cellular decision making, whether or not a specific gene is turned on. However, the language embedded in the biology of the histones is still poorly understood such as the role of each modification and how it translates to a cellular event. This remains a fundamental question in the current field of molecular biology.
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Genetic alterations
Numerous histone modification factors have now been found in individuals with neurodevelopmental disorders. The relative abundance of these mutations suggests that accurate readout of histone modifications network is essential during brain development and also for normal brain function. However, the mechanistic relationship between mutations in histone modification pathways and neurodevelopmental disorders remains unknown. Developing an understanding of these mechanisms will be invaluable for future therapeutic strategies for IDs. We thus aim to elucidate these processes at both a molecular and cellular level.
