Scientists create first map of DNA modification in 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 critical role. This work offers new insights into how early brain development shapes mental health throughout life.

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

He created the first map of DNA modification in the hippocampus and prefrontal cortex, two brain regions essential for learning, memory and emotional regulation. These areas are also frequently implicated in disorders like autism and schizophrenia.

The researchers hope that the data resource, which they have made public through an online platform, will be a valuable tool that scientists can use to link genetic variants associated with these diseases to the most common genes, cells and developmental periods. more sensitive to their effects. .

“Neuropsychiatric disorders, even those with adult onset, often arise from genetic factors disrupting early brain development,” said Luo, a member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at ‘UCLA. “Our map provides a baseline to compare to genetic studies of diseased brains and identify when and where molecular changes occur.”

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

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

Understanding how these two regulatory elements act on genes that affect development is a crucial step in understanding how errors in this process lead to neuropsychiatric disorders.

“The vast majority of pathogenic variants we identified are located between genes on the chromosome, so it is difficult to know which genes they regulate,” said Luo, who is also an assistant professor of human genetics at the David Geffen School in Medicine at UCLA.

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

For example, autism spectrum disorders are commonly diagnosed in children ages 2 and older. However, if researchers can better understand the genetic risk of autism and its impact on development, they can potentially develop intervention strategies to help alleviate autism symptoms, such as communication problems, during brain development.

The research team analyzed more than 53,000 brain cells from donors ranging from mid-gestation to adulthood, revealing significant changes in gene regulation during critical developmental windows. By capturing such a broad spectrum of developmental phases, the researchers were able to paint a remarkably comprehensive picture of the massive genetic rewiring that occurs at critical times in human brain development.

One of the most dynamic times is midway through pregnancy. At this point, neural stem cells called radial glials, which produced billions of neurons during the first and second trimesters, stop producing neurons and begin generating glial cells, which support and protect the neurons.

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

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

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

“The links we identified in different cell types through this work could address current challenges in identifying meaningful genetic risk factors for neurodevelopmental and neuropsychiatric diseases.”

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

“Developing a healthy human brain is a tremendous feat,” says co-author Dr. Joseph Ecker, a Salk Institute professor and Howard Hughes Medical Institute investigator.

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