Friday, April 4, 2025
4/4/2025
Epigenetic regulation of the neuroendocrine axis in brain development and behavior - PROJECT SUMMARY Lysine methyltransferase 5B (KMT5B) is part of a gene family that modulates the methylation state of histone 4 lysine 20 (H4K20) residues, and H4K20 methylation regulates gene expression by altering chromatin compaction. Heterozygous disruptive variants in KMT5B have been associated with human neurodevelopmental disease–specifically, KMT5B has been identified as one of the most mutated genes in autism spectrum disorder (ASD), a highly prevalent and lifelong condition. Phenotypes reported among KMT5B patients and in our Kmt5b mouse model suggest that KMT5B may have a role in the epigenetic expression of the insulin-like growth factor (IGF) family, which includes two members–IGF1 and IGF2. These hormones can be expressed in an endocrine (circulating) or paracrine (local) fashion and have been strongly linked to autism. We hypothesize that KMT5B regulates the expression of the IGF genes driving the primary neurodevelopmental phenotypes observed. We will test our central hypothesis and, thereby, accomplish the overall objective of this project through three specific aims. First, we will specify the role that KMT5B plays in paracrine IGF production (i.e., local brain expression) using both constitutive and brain-specific knockout models. Second, we will define how endocrine IGF expression (i.e., circulating and expressed postnatally by the liver) changes relative to KMT5B expression over time and how this impacts (1) brain IGF expression and (2) KMT5B-linked behavioral phenotypes. We will compare the results of these two aims to identify whether IGF1 and IGF2 are differentially or similarly regulated by KMT5B and whether rescue can be achieved by targeting either system. Finally, we will use a combination of ATAC seq and RNA seq to identify cell types where KMT5B regulates the expression of IGFs and whether these effects can be therapeutically rescued. Our results will increase our understanding of how KMT5B interacts with the IGF axis, how IGFs are epigenetically regulated, and how IGF1 and IGF2 are regulated in different tissues over time. We expect the outcomes of this study to define the contribution of KMT5B to autism clinical features while illuminating novel drug targets for the treatment of this clinical population.
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