Neutralizing epigenomes in neurodevelopmental disorders

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): In neurodevelopmental disorders such as intellectual disabilities (ID) and autism spectrum disorders (ASD), a large number of mutations in more than 30 regulators of posttranslational modification on histones have recently been found. Intricate regulation of the histone modifications, therefore, appears to be essential for proper cognitive development. However, because little is known about how these mutations lead to IDs and ASDs, no rationale therapeutic options are available for the patients. The long-term research goal of my laboratory is to elucidate histone modification-mediated mechanisms underpinning normal and pathological brain development and function. Mutations in KDM5C account for at least up to 2% of X-linked ID (XLID). Patients with these mutations often show epilepsy and aggressive behaviors. We previously discovered that KDM5C encodes the first eraser enzyme for di- and trimethylated histone H3 lysine 4 (H3K4me2/3). Missense mutations associated with ID de- crease the demethylase activity, suggesting that the mutations lead to loss of function. More recently, we found that Kdm5c-deficient mice closely recapitulate behavioral abnormalities of human patients, including impaired learning ability and profound aggression. The Kdm5c-deficient mice are the first mouse model of ID, which is caused by defective erasure of histone modifications. Our work was the first to link the dynamic nature of his- tone methylation to human cognitive development. To be removed by KDM5C, the H3K4me marks are placed by a group of H3K4me writer enzymes. In humans, seven H3K4me writer enzymes are reported to place H3K4me marks, whereas six enzymes including KDM5C remove H3K4me. However, the functional relation- ships between KDM5C and any of the H3K4me writer enzymes for H3K4me are not known. The proposed study will address the fundamental question, How and where in the genome does the balancing act between writers and erasers of histone modifications ensure cognitive development and function? The specific goal of the proposed research is to elucidate the functional dynamics between KDM5C, an H3K4me eraser, and H3K4me writer enzymes. We will systematically identify the H3K4me writer enzymes that counteracts with KDM5C at molecular, cellular, and behavioral levels. Completion of the work will likely provide a potential drug target of ID. Because virtually all histone modifications are dynamically placed and erased, our approach might be broadly applicable to many other human diseases that involve dysregulation of histone modification. Importantly, the research will be the first to reveal interplay between specific epigenetic writers and erasers during neuronal development.