Interplay of Histone Methyl Writers and Erasers in the Brain

[摘要] Dysregulation of histone methylation has emerged as a major contributor of neurodevelopmental disorders (NDDs) such as autism and intellectual disability. Methylation of histone H3 lysine 4 (H3K4me) is an extensively regulated post-translational modification with 13 writer and eraser enzymes modulating this mark, nine of which are mutated in human NDDs to date. However, roles of H3K4 methylation and demethylation in the central nervous system are not well understood. My thesis research aims to address this gap in knowledge and gain insight into the interplay of H3K4me-specific chromatin regulators in normal and pathologic brain development. We propose that H3K4me balance is critical for proper cognitive development, and that H3K4me-regulators orchestrate developmental programs in the brain by fine-tuning methylation at key genomic loci. We also posit the opposite nature of writer-eraser enzymes reveals a potential for enzyme activity modulation to ;;neutralize” histone methylation and serve as a therapeutic. The work in this dissertation focuses on H3K4me writer and eraser duo KMT2A and KDM5C, responsible for human NDDs Wiedemann-Steiner Syndrome (WDSTS) and mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ), respectively. Mouse models of each recapitulate the cognitive and behavioral impairments characteristic of the respective human disorders, yet mechanistic studies of how KDM5C and KMT2A affect the brain are lacking. I reported a new MRXSCJ-associated human mutation in KDM5C that specifically compromises gene-regulatory function but not enzymatic activity or stability, suggesting non-enzymatic roles for KDM5C and a new pathological mechanism for loss-of-function mutations. To explore the roles of KMT2A and KDM5C in the brain, I systematically characterized Kmt2a- and Kdm5c-deficient mice at molecular, cellular, and behavioral levels. We show similar phenotypes between Kmt2a- and Kdm5c-mutant male mice, including altered transcriptomes and impaired dendritic morphology in amygdala, and increased aggressive behaviors, revealing commonalities despite loss of opposite H3K4me regulators. I generated Kmt2a-Kdm5c-double-mutant mice to determine if pairwise relationships between opposing enzymes could ;;neutralize” histone methylation and specifically combat loss of the opposite enzyme to ameliorate disease phenotype(s). We observed a clear reversal in double mutant male mice of neuron morphology and behavior deficits, and partially corrected H3K4me3 landscapes and transcriptomes. Female double mutant mice exhibited exacerbated fear memory deficits, and rescued social behaviors.Together, the studies in this dissertation reveal functional consequences of altered KMT2A and KDM5C function, both individually and in concert, in the central nervous system, and provide the field with a proof-of-principle concept of opposing enzyme dual modulation to combat their associated disorders.

[发布机构] University of Michigan

[效力级别] chromatin

[关键词] genetics;chromatin;neurodevelopmental disorders;epigenetics;autism;intellectual disability;Genetics;Science;Human Genetics