A recent study has produced a detailed map of DNA modifications in two important areas of the brain associated with learning, memory, and emotional regulation. This map serves as a crucial reference point to ensure that stem cell-based models accurately reflect human brain development.
A research team from UCLA has made groundbreaking discoveries about the evolution of gene regulation during human brain development. Their findings highlight the significance of the 3D arrangement of chromatin, which consists of DNA and proteins, in this process. This research sheds light on how the early stages of brain development can influence mental health later in life.
The study, which was published in Nature, 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. They successfully created the first detailed map of DNA modifications in the hippocampus and prefrontal cortex—the two brain regions essential for learning, memory, and regulating emotions. These areas are often linked to disorders such as autism and schizophrenia.
The team aims for their publicly available data resource to serve as a valuable tool for researchers to link genetic variations associated with these disorders to the specific genes, cells, and critical developmental stages that are most affected.
“Many neuropsychiatric disorders, even those appearing in adulthood, are often caused by genetic factors that disrupt early brain development,” said Luo, who is part of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Our map creates a standard for comparing genetic studies of affected brains, allowing us to identify when and where molecular changes take place.”
To create this map, the researchers utilized an advanced sequencing method developed by Luo, known as single nucleus methyl-seq and chromatin conformation capture (snm3C-seq). This technique lets scientists examine two epigenetic mechanisms influencing gene expression at the single-cell level: the chemical alterations to DNA termed methylation and the chromatin’s structure, which determines how DNA is organized within the nucleus.
Understanding how these regulatory factors act upon genes essential for development is vital in determining how disruptions in this process can lead to neuropsychiatric disorders.
“The majority of harmful genetic variants we have identified are situated between genes on chromosomes, complicating the task of linking them to specific genes,” explained Luo, who is also an assistant professor of human genetics at the David Geffen School of Medicine at UCLA. “By investigating the way DNA is organized in individual cells, we are able to discover connections between genetic variants and particular genes, helping us to identify cell types and developmental phases that are especially susceptible to these disorders.”
As an illustration, autism spectrum disorder is typically diagnosed in children aged 2 and older. If researchers can better understand the genetic factors contributing to autism and their impact on development, they may be able to create intervention strategies to ease symptoms, such as communication difficulties, during critical developmental phases.
The research team assessed over 53,000 brain cells from donors ranging from mid-gestation to adulthood, uncovering significant changes in gene regulation during important developmental milestones. By encompassing a wide array of developmental stages, the researchers were able to compile an extensive depiction of the substantial genetic reorganization that occurs at key points in human brain development.
One particularly active period occurs around the middle of pregnancy when neural stem cells known as radial glia stop producing neurons and instead begin generating glial cells that protect and support neurons. Concurrently, the new neurons mature, acquiring necessary traits to perform specific functions and establishing synaptic connections for communication.
This developmental phase has been largely overlooked in earlier research due to the scarcity of brain tissue samples from this timeframe.
“Our study addresses the complex relationship between DNA organization and gene expression in the developing human brain during periods that have often been neglected: the third trimester and infancy,” stated Paredes, an associate professor of neurology at UCSF. “The links we have uncovered across various cell types could help clarify current challenges in pinpointing significant genetic risk factors for neurodevelopmental and psychiatric disorders.”
The results also carry implications for enhancing stem cell-based models, such as brain organoids, used to study brain development and related diseases. The new map will serve as a benchmark for scientists to verify that these models accurately represent human brain development.
“Developing a healthy human brain is an incredible challenge,” states co-author Dr. Joseph Ecker, a professor at the Salk Institute and an investigator with the Howard Hughes Medical Institute. “Our study creates a critical database that captures significant epigenetic alterations during brain development, bringing us closer to understanding where and when failures in this process may lead to conditions like autism.”
The research received support from the National Institutes of Health’s BRAIN Initiative Cell Atlas Network (BICAN), which aims to develop reference brain cell atlases to lay a foundational framework for exploring brain function and diseases.
Funding for the study was also provided by several organizations, including the National Institute of Mental Health, the National Human Genome Research Institute, the Simons Foundation, the Roberta and Oscar Gregory Endowment in Stroke and Brain Research, the Chan Zuckerberg Biohub, the National Research Foundation of Korea, the Shurl and Kay Curci Foundation, the National Institute on Drug Abuse, and the California Institute for Regenerative Medicine.
Additional contributors include: Jingtian Zhou, Yi Zhang, Dong-Sung Lee, Kangcheng Hou, Oier Pastor Alonso, Kevin D Abuhanna, Joseph Galasso, Colin Kern, Chu-Yi Tai, Carlos Garcia Padilla, Mahsa Nafisi, Yi Zhou, Anthony D. Schmitt, Terence Li, Maximilian Haeussler, Brittney Wick, Martin Jinye Zhang, Fangming Xie, Ryan S. Ziffra, Eran A. Mukamel, Eleazar Eskin, Tomasz J. Nowakowski, Jesse R. Dixon, Bogdan Pasaniuc, Joseph R. Ecker, Quan Zhu, and Bogdan Bintu.
