Role of KMT2D in neurodevelopmental disorders

The proposed research and training program aims to equip the PI with the skills to become an independent investigator and to advance the understanding of neurodevelopmental disorders (NDDs) while developing innovative therapies. Building on previous training in epigenomics, the PI will use emerging single-cell epigenomic technologies to link pathogenic variants in chromatin regulators to specific neuronal phenotypes. NDDs affect more than 3 million people in the U.S., impairing language, learning, motor skills, and neurological function. Despite their prevalence, the molecular mechanisms underlying these disorders are not well understood, hindering the development of effective treatments. Mutations in chromatin regulators, such as KMT2D, are major contributors to NDDs, including intellectual disability, autism spectrum disorder and schizophrenia. KMT2D is essential for differentiation and development by modulating chromatin accessibility and 3D chromatin structure. Loss-of-function mutations in KMT2D are associated with brain malformations, memory defects and neuronal differentiation problems, with Kabuki syndrome being a notable example. However, the precise molecular mechanisms by which KMT2D haploinsufficiency leads to brain abnormalities and cognitive impairment are not well understood. This project will use mouse and human models of KMT2D haploinsufficiency to profile single cell chromatin accessibility and 3D chromatin structure, and examine the impact on regulatory programs in different cell types. The research and training will be guided by a distinguished mentoring team of experts in several relevant fields: Drs. Walsh (neurobiology), Bodamer (NDDs), Lee (single cell genomics), and Gussoni (stem cells). The results of the project will advance our understanding of chromatin regulators in NDDs and provide broadly applicable methods and tools for other NDDs. Project Number: 1K01NS142019-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Youngsook Jung | Institution: BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | Award Amount: $241,380 | Activity Code: K01 | Study Section: Neurological Sciences Training 3 Study Section[NST-3] View on NIH RePORTER: https://reporter.nih.gov/project-details/11114575