West LA Times

A UCLA-led study has produced the first map of DNA modification in the human brain, focusing on two regions vital for learning, memory, and emotional regulation. This research offers a benchmark for ensuring stem cell-based models accurately replicate human brain development.

The study was led by Dr. Chongyuan Luo at UCLA and Dr. Mercedes Paredes at UC San Francisco, with contributions from researchers at the Salk Institute, UC San Diego, and Seoul National University. It was published in Nature and provides insights into how early brain development influences lifelong mental health.

Dr. Luo stated that "neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development." The map serves as a baseline to compare against genetic studies of disease-affected brains to pinpoint when and where molecular changes occur.

The team used a sequencing approach developed by Dr. Luo called single nucleus methyl-seq and chromatin conformation capture (snm3C-seq). This technique allows simultaneous analysis of DNA methylation and chromatin conformation on a single-cell basis.

The research involved analyzing over 53,000 brain cells from donors ranging from mid-gestation to adulthood. Significant changes in gene regulation were observed during critical developmental windows. One key period identified is around the midpoint of pregnancy when neural stem cells transition from producing neurons to generating glial cells.

Dr. Paredes noted that their study addresses "the complex relationship between DNA organization and gene expression in developing human brains at ages typically not interrogated: the third trimester and infancy."

This work also aims to improve stem cell-based models like brain organoids used for studying brain development and diseases. Co-author Dr. Joseph Ecker emphasized that their study establishes an important database capturing key epigenetic changes during brain development.

The project received support from various organizations including the National Institutes of Health’s BRAIN Initiative Cell Atlas Network (BICAN), the National Institute of Mental Health, and others.

Additional authors 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 among others.