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.

Public Health Relevance

The mis-regulation of post-transcriptional modifications on histone proteins has been found in human neurodevelopmental disorders, such as intellectual disabilities and autism spectrum disorders. This project aims to uncover developmental interaction between enzymes that deposit or erase a specific histone modification. The obtained knowledge will be a foundation upon which to develop therapeutic strategies for a prevalent form of intellectual disability caused by mutation of a histone modification eraser, KDM5C.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089896-04
Application #
9479301
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Riddle, Robert D
Project Start
2015-06-15
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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