Project Summary Intellectual and developmental disabilities (IDDs) cause immense suffering and affect almost 3% of the U.S. population. Nearly 1,000 IDD-associated genes have been identified, but this is far too many to study individually and develop custom therapies for each. An alternative approach is to divide IDD-associated genes into subgroups based on shared pathways or convergent mechanisms, an idea I will test in this proposal by studying chromatin modifiers, which account for nearly 20% of IDD-associated genes. Specifically, I will focus on the COMPASS (Complex of Proteins Associated with SET1) family of methyltransferases, the largest group of chromatin remodelers involved in IDD. Humans have six COMPASS complexes, all of which methylate H3K4, a histone modification associated with active transcription. Haploinsufficiency of any of the core DNA-binding proteins of these COMPASS complexes—SETD1A, SETD1B, KMT2A, KMT2B, KMT2C, and KMT2D—causes IDD. Identifying convergent mechanisms across many genes requires a system that enables high-throughput genetic perturbations and mitigates confounding variables. I will thus use human iPSC-derived neurons (iNeurons) as a homogeneous system to model haploinsufficiency via CRISPR interference (CRISPRi). In Aim 1, I will determine transcriptomic changes caused by COMPASS methyltransferase haploinsufficiency in human iNeurons. I will test whether there is a significant overlap between dysregulated genes and pathways across the six COMPASS gene knockdowns. In Aim 2, I will use CUT&RUN to identify epigenetic perturbations in each methyltransferase haploinsufficiency model. In Aim 3, I will characterize the effects of COMPASS methyltransferase haploinsufficiency on neuronal morphology and electrophysiology. I will then perform a small- molecule screen to determine if histone demethylase inhibitors can rescue any of these phenotypes through rebalancing H3K4 methylation. These experiments will elucidate the pathobiology of COMPASS-related IDDs, identify pathways for therapeutic intervention, and establish cellular disease models for testing candidate therapies. Although this proposal focuses on six genes, it will also establish a broad framework for studying the convergence of hundreds of other IDD risk genes, which would accelerate the discovery of viable therapeutic approaches for some of the world’s most disabled patients.