The Structural Biology of Autism: Chromatin Remodeling and the Control of Transcription in the Context of Autism

On June 27, 2024, the NLM Family Foundation hosted a Boston Club meeting titled, “The Structural Biology of Autism: Chromatin Remodeling and the Control of Transcription in the Context of Autism.” The meeting was chaired by Prof. Clarence E. Schutt, Director & Chief Scientific Officer of the NLM Family Foundation.

The Foundation’s interest in this topic stems from the fact that after a quarter century of intensive efforts from laboratories around the world, the role of genetic mutations involved in the etiology of autism have been largely delineated. Well over a hundred genes have been identified that are known to affect two fundamental biological processes: synaptic plasticity and chromatin remodeling. Previous Boston Clubs have taken up the question of how impaired synapses affect neurodevelopment and the normal functioning of global neuronal circuits in sensory, motor, and speech activities, contributing to the symptoms of autism. CHD8, a member of a class of proteins known as chromatin remodelers, has emerged as one of the most important non-synaptic proteins contributing to autism.

In the cell nucleus, DNA comprising genes are packaged in nucleosomes in which 146 base pairs wrap around a core of histone proteins. Nucleosomes themselves are arranged into densely-packed higher order structures which need to be opened up to allow access for RNA polymerase to transcribe genes into the messenger RNA that is read by ribosomes to produce proteins. During memory formation, for example, when neurons need a fresh supply of protein to re-shape synapses, CHD8 is activated to pry open nucleosomes to initiate the remodeling of chromatin.  Impairment due to mutation of this process can lead to serious problems during neurodevelopment and sensory, motor, and language processing.

Structural Biology is the science of discovering the molecular structures of proteins and protein-DNA complexes, as well as a host of other entities that make up cells and organelles. Structures at atomic resolution can be used to design drugs and address the ramifications of mutations in essential proteins.

This Boston Club explored recent developments in the field of chromatin remodeling and transcriptional regulation with a specific emphasis on high resolution protein structures known to be important for understanding autism.

2024

The Nancy Lurie Marks Family Foundation, Wellesley, MA