Scientists create the first map of DNA modification in the developing human brain

A UCLA-led study has provided unprecedented insight into how gene regulation evolves during human brain development, showing how the 3D structure of chromatin (DNA and proteins) plays a crucial role. This work provides new insights into how early brain development determines lifelong mental health.

The study, published in Naturewas led by Dr. Chongyuan Luo from UCLA and Dr. Mercedes Paredes of UC San Francisco, in collaboration with researchers from the Salk Institute, UC San Diego and Seoul National University.

It created the first map of DNA modification in the hippocampus and prefrontal cortex – two brain regions crucial for learning, memory and emotional regulation. These areas are also often involved in conditions such as autism and schizophrenia.

The researchers hope that the data source, which they have made publicly available through a online platformwill be a valuable tool that scientists can use to connect genetic variants linked to these conditions to the genes, cells and developmental periods most sensitive to their effects.

“Neuropsychiatric disorders, even those that emerge in adulthood, often arise from genetic factors that disrupt early brain development,” said Luo, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Our map provides a baseline to compare with genetic studies of disease-affected brains and determine when and where molecular changes occur.”

To produce the map, the research team used an advanced sequencing approach that Luo developed and scaled with support from the UCLA Broad Stem Cell Research Center Flow Cytometry Core, called single nucleus methyl-seq and chromatin conformation capture, or snm3C-seq .

This technique allows researchers to simultaneously analyze two epigenetic mechanisms that control gene expression on a single-cell basis: chemical changes in DNA, known as methylation, and chromatin conformation, the 3D structure of how chromosomes are tightly folded to fit into nuclei.

Figuring out how these two regulatory elements interact with genes that influence development is a crucial step in understanding how errors in this process lead to neuropsychiatric disorders.

“The vast majority of disease-causing variants we identified are located between genes on the chromosome, so knowing which genes they regulate is challenging,” said Luo, who is also an assistant professor of human genetics at the David Geffen School of Science. Medicine at UCLA.

“By studying how DNA is folded in individual cells, we can see where genetic variants connect to certain genes, which can help us identify the cell types and developmental periods most vulnerable to these conditions.”

For example, autism spectrum disorder is often diagnosed in children aged 2 years and older. However, if researchers can better understand the genetic risk of autism and how it affects development, they may be able to develop intervention strategies to alleviate autism symptoms, such as communication problems, as the brain develops.

The research team analyzed more than 53,000 brain cells from donors from mid-pregnancy through adulthood, revealing significant changes in gene regulation during critical stages of development. By capturing such a broad spectrum of developmental stages, the researchers have managed to paint a remarkably comprehensive picture of the massive genetic rewiring that takes place during critical times in human brain development.

One of the most dynamic periods occurs around mid-pregnancy. At this time, neural stem cells called radial glia, which produced billions of neurons during the first and second trimesters, stop producing neurons and begin generating glial cells, which support and protect neurons.

At the same time, the newly formed neurons mature, giving them the characteristics they need to perform specific functions and form the synaptic connections that allow them to communicate.

This stage of development has been overlooked in previous studies, the researchers say, due to the limited availability of brain tissue from this period.

“Our study addresses the complex relationship between DNA organization and gene expression in the developing human brain at ages not typically interrogated: the third trimester and childhood,” said Paredes, associate professor of neurology at UCSF.

“The connections we identified through this work between different cell types could disentangle current challenges in identifying meaningful genetic risk factors for neurological and neuropsychiatric disorders.”

The findings also have implications for improving stem cell-based models, such as brain organoids, used to study brain development and diseases. The new map provides scientists with a benchmark to ensure these models accurately mimic human brain development.

“Growing a healthy human brain is a huge achievement,” says co-author Dr. Joseph Ecker, professor at the Salk Institute and investigator of the Howard Hughes Medical Institute.

“Our study provides an important database that captures important epigenetic changes that occur during brain development, bringing us closer to understanding where and when errors occur in this development that can lead to neurodevelopmental disorders such as autism.”