BRD1 haploinsufficiency alters early neuronal programming and disrupts maturation in human induced glutamatergic neurons

Abstract

BRD1 is an epigenetic regulator implicated in neurodevelopmental and psychiatric disorders, yet its role in human neuronal differentiation, maturation, and function remains poorly understood. Here we show that BRD1 haploinsufficiency disrupts early neuronal programming, resulting in accelerated maturation and altered neurodevelopmental trajectories in human induced glutamatergic neurons. Transcriptomic profiling reveals an early shift toward neuronal identity, characterized by downregulation of pluripotency markers and persistent upregulation of genes involved in synapse assembly and organization, including GRIA3. Despite this, BRD1+/- neurons form significantly smaller synapses and display increased neuronal activity. Our findings highlight BRD1 as a key regulator of neurodevelopmental timing and synaptic maturation, and network activity reinforcing growing evidence that disruptions in chromatin-mediated control of differentiation and synaptic organization contribute to neurodevelopmental disorders.