Mechanistic dissection of three-dimensional regulatory architecture in neurodevelopmental disorders

2019 Scientific Innovations Award
Michael E. Talkowski, Ph.D.
Harvard University

Among the most intriguing discoveries to emerge from technological advances in recent years are the insights into how the three-dimensional (3D) structure of the genome influences many aspects of local and long-range gene regulation and function. These data suggest that identifying the specific changes in the genetic code through sequencing is insufficient to predict which mutations will influence gene function and potentially cause disease; instead, one must interpret mutations in the context of 3D DNA folding. In this proposal, we seek to explore for the first time the regulatory impact of structural changes to 3Db organization on genes expressed early in brain development and associated with severe neurodevelopmental anomalies. These studies will thus attempt to couple the regulatory influence of 3D genome organization with strongly deleterious mutations in the noncoding genome, which taken together could have profound implications for human disease studies of neurodevelopmental and neuropsychiatric disorders. These studies will begin to parse the areas of chromosomes sensitive to changes in 3D organization and known to contribute to neurodevelopmental disorders (e.g. segments associated with human genomic disorders). To do this, we will utilize genome editing approaches in induced pluripotent stem cell models of human neural tissue. Our goal is to identify functional elements within these genomic disorder segments that are indirectly required to fine-tune expression of genes necessary in brain development over long distances in the genome. We will dissect the 3D structures that enable this long- range regulation, such as localized DNA folding that create genetic microenvironments called topologically associating domains (TADs), to pinpoint precisely which regulatory elements are driving expression of the genes within these genomic disorder segments. This study is the first to directly model structural rearrangements of the genome in human neural tissue to determine whether disrupting noncoding segments of DNA responsible for proper 3D folding can be as damaging as direct gene mutations. Our preliminary data suggests that such changes may underlie a novel noncoding mechanism as a cause of human genomic disorders, and deciphering the genomic architecture that drivers such long- range mechanisms could open the field to exploring entire classes of novel etiological risk factors in human neurological disorders, particularly those that occur early in neurodevelopment.

Other Awards

Angelique Bordey, Ph.D., Yale University
The Role of Ribosomes in Synaptic Circuit Formation and Socio-Communicative Deficits
Our proposal aims at identifying a molecular mechanism responsible for autism-like socio-communicative defects in the developmental disorder, tuberous sclerosis complex (TSC). TSC is a genetic disorder with a 30-60% incidence…
Adam E. Cohen, Ph.D., Harvard University
To spike or not to spike? Mapping dendritic computations in vivo.
The brain is made of neurons, and neurons convert synaptic inputs to spiking outputs. How does a neuron decide when to spike?
Gina Turrigiano, Ph.D., Brandeis University
Homeostatic Maintenance of Neocortical Excitation-inhibition Balance by Ciliary Neuropeptidergic Signaling
Brain circuit wiring is adjusted during adolescence to generate fully functional circuits, and this process depends on an interaction between genetics and experience. During this period of experience-dependent development, excitatory…
Gregory Scherrer, Ph.D., The University of North Carolina at Chapel Hill
Mechanisms of Affective States and Drug Discovery at the Intersection of Chronic Pain and Opioid Addiction
Pain is normally a sensation that we experience when our body is exposed to damaging stimuli, such as the noxious heat of an open flame. However, when chronic, pain becomes…