Healthcare (Commonwealth Union) – A groundbreaking study led by UCLA has offered a fresh perspective on how gene regulation changes throughout human brain development, highlighting the vital role of chromatin’s 3D structure—comprising DNA and proteins. The research sheds new light on how early brain development influences mental health across a lifetime.
Published in Nature, the study was spearheaded by Dr. Chongyuan Luo from UCLA and Dr. Mercedes Paredes from UC San Francisco, alongside collaborators from the Salk Institute, UC San Diego, and Seoul National University. The team produced the first-ever map of DNA modifications in the hippocampus and prefrontal cortex—key brain regions involved in learning, memory, and emotional control, as well as disorders such as autism and schizophrenia.
The researchers have made the data publicly accessible through an online platform, aiming to provide a valuable resource for scientists. This tool will help link genetic variants tied to these conditions with the genes, cells, and critical developmental stages most affected by them.
“Neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development,” explained Luo, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Our map offers a baseline to compare against genetic studies of disease-affected brains and pinpoint when and where molecular changes occur.”
To create the map, the research team employed a state-of-the-art sequencing technique developed by Luo and expanded with assistance from the UCLA Broad Stem Cell Research Center Flow Cytometry Core. Known as single nucleus methyl-seq and chromatin conformation capture (snm3C-seq), this method allows for the simultaneous analysis of two key epigenetic processes at the single-cell level: DNA methylation, a chemical modification of DNA, and chromatin conformation, which refers to the 3D organization of chromosomes within the cell nucleus.
Researchers of the study pointed out that having the knowledge of how these two regulatory mechanisms influence gene expression during development is essential to uncovering how disruptions in this process contribute to neuropsychiatric disorders.
“The vast majority of disease-causing variants we’ve identified are located between genes on the chromosome, so it’s challenging to know which genes they regulate,” explained Luo, who is an assistant professor of human genetics at the David Geffen School of Medicine at UCLA as well. “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.”
Autism spectrum disorder is often diagnosed in children as young as 2 years old. However, if scientists can better understand the genetic factors that contribute to autism and how they affect brain development, they may be able to create early interventions to address symptoms such as communication difficulties while the brain is still forming.
The research team studied over 53,000 brain cells from donors at various stages of development, from mid-pregnancy to adulthood. Their analysis uncovered significant shifts in gene regulation during crucial windows of brain development. By examining such a wide range of developmental stages, the researchers gained a detailed view of the extensive genetic changes that occur during key moments in brain formation.
Researchers indicated that one of the most critical periods happens midway through pregnancy. During this time, neural stem cells known as radial glia, which have produced billions of neurons in the first and second trimesters, stop making neurons and begin creating glial cells. These glial cells help support and protect neurons. Meanwhile, the newly generated neurons mature, developing the features necessary to perform their specific roles and forming the synaptic connections that allow them to communicate.
According to the researchers, this phase of development has been largely overlooked in past studies because of the scarcity of brain tissue samples from this time.
