A Neuron-specific Methyl-histone Regulatory Complex

Project Summary This project aims to unravel the unique chromatin regulation mechanisms in neurons and their role in neurodevelopmental disorders. Mutations in chromatin regulators are frequent causes of neurodevelopmental disorders such as intellectual disabilities, autism, and schizophrenia. The abundance of chromatin regulator mutations poses a question: why is the brain so vulnerable to chromatin dysregulation? The molecular basis of this vulnerability remains elusive, which prevents the understanding of the etiology of neurodevelopmental disorders. Our previous work identified 14 chromatin regulator genes undergoing neuron-specific mRNA splicing, including LSD1 and PHF21A, which form a complex within neurons. We discovered that neuronal splicing events in LSD1 and PHF21A impair nucleosome binding and reduce H3K4 demethylation activity. The neuronal PHF21A variant prevents excessive synapse formation. Building on these findings, we propose to investigate: 1. The recruitment of the neuronal LSD1-PHF21A complex by MYT1L, a neuron-specific transcription factor, to regulate gene expression during neuronal maturation. 2. The interplay between non-CpG methylation and the neuronal LSD1-PHF21A complex in regulating gene promoters. 3. The structural and functional differences between canonical and neuronal LSD1-PHF21A complexes, focusing on the role of HMG-box DNA binding proteins BRAF35 and iBRAF. Our research will employ biochemistry, functional genomics, neuronal morphological analyses, genome-wide methylation analysis, and structural biology techniques. We expect to gain insights into how neuronal splicing of broadly expressed chromatin factors cooperates with neuron-specific chromatin regulators and transcription factors. This study is expected to improve our understanding of neuron-specific chromatin regulation and its implications in neurodevelopmental disorders, potentially leading to new therapeutic strategies for conditions associated with chromatin dysregulation in the brain.