New Insights Into Early Brain Development and Mental Health

A study led by UCLA has provided insights into how gene regulation changes during human brain development. It demonstrates the crucial role played by the 3D structure of chromatin, which is made up of proteins and DNA. This research provides fresh perspectives on how early brain development affects mental health throughout life.

Researchers from the Salk Institute, UC San Diego, Seoul National University, and Drs. Chongyuan Luo and Mercedes Paredes of UCLA and UC San Francisco conducted the study, published in Nature.

The study produced the first map of DNA alteration in the prefrontal cortex and hippocampal regions, two areas of the brain essential for memory, learning, and emotional control. These areas are frequently implicated in illnesses such as schizophrenia and autism.

The data resource, which the researchers have made publically accessible via an online platform, is intended to be a useful tool for scientists to link genetic variants linked to these disorders to the genes, cells, and developmental stages most susceptible to their impacts.

Neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development. Our map offers a baseline to compare against genetic studies of diseased-affected brains and pinpoint when and where molecular changes occur.”

Chongyuan Luo, Assistant Professor, Department of Human Genetics, University of California

Luo is also a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

The study team created the map by employing single nucleus methyl-seq and chromatin conformation capture, or snm3C-seq, a state-of-the-art sequencing technique that Luo created and scaled with assistance from the UCLA Broad Stem Cell Study Center Flow Cytometry Core.

Using this method, scientists may simultaneously examine two epigenetic processes that govern gene expression at the single-cell level: methylation, which is the chemical modification of DNA, and chromatin conformation, which is the three-dimensional arrangement of chromosomes that are tightly folded to fit into nuclei.

Understanding how faults in this pathway result in neuropsychiatric diseases requires an understanding of how these two regulatory factors work on genes that affect development.

Chongyuan Luo said, “The vast majority of disease-causing variants we have identified are located between genes on the chromosome, so it is challenging to know which genes they regulate. By studying how DNA is folded inside of individual cells, we can see where genetic variants connect with certain genes, which can help us pinpoint the cell types and developmental periods most vulnerable to these conditions.”

Chongyuan Luo is also an Assistant Professor in the Department of Human Genetics at, the University of California.

For instance, children two years of age and older are frequently diagnosed with autism spectrum condition, but if scientists can learn more about the genetic predisposition to autism and how it affects development, they might be able to create intervention plans that help reduce the symptoms of autism, such as difficulties with communication, while the brain is still growing.

After examining over 53,000 brain cells from donors who were between the middle of pregnancy and adulthood, the research team discovered notable alterations in gene regulation throughout crucial developmental windows.

The researchers were able to put together a very complete picture of the huge genetic rewiring that takes place throughout crucial time points in human brain development because they were able to capture such a broad spectrum of developmental phases.

One of the most active times of pregnancy is around the halfway point. During the first and second trimesters, neural stem cells known as radial glia develop billions of neurons. At this point, however, they cease producing neurons and start forming glial cells, which support and shield neurons.

Simultaneously, the newly created neurons grow, acquiring the properties required to carry out particular tasks and creating the synaptic connections necessary for communication.

The researchers claim that earlier studies disregarded this developmental stage due to the scarcity of brain tissue from this era.

Our study tackles the complex relationship between DNA organization and gene expression in the developing human brain at ages typically not interrogated: the third trimester and infancy. The connections we have identified across different cell types through this work could untangle the current challenges in identifying meaningful genetic risk factors for neurodevelopmental and neuropsychiatric conditions.”

Mercedes F. Paredes, Associate Professor, David Geffen School of Medicine, University of California

The results may also impact the development of stem cell-based models for studying brain development and disorders, such as brain organoids. Scientists can use the new map as a standard to ensure that these models faithfully represent the development of the human brain.

Growing a healthy human brain is a tremendous feat. Our study establishes an important database that captures key epigenetic changes that occur during brain development, in turn bringing us closer to understanding where and when failures arise in this development that can lead to neurodevelopmental disorders like autism.”

Dr. Joseph Ecker, Study Co-Author and Professor, The Salk Institute for Biological Studies