Gene Regulation Mapped in Developing Human Brain

A collaborative study led by UCLA researchers has provided a look at how gene regulation evolves during human brain development. Their comprehensive map provides valuable insights into how early brain development influences lifelong mental health.

The research team, headed by Chongyuan Luo from UCLA and Mercedes Paredes from UCSF, focused on the hippocampus and prefrontal cortex—brain regions crucial for learning, memory, and emotional regulation. These areas are often implicated in disorders such as autism and schizophrenia.

Using an advanced sequencing technique called snm3C-seq, the researchers analyzed over 53,000 brain cells from donors ranging from mid-gestation to adulthood. This method allowed them to simultaneously examine DNA methylation and chromatin conformation, two key epigenetic mechanisms controlling gene expression.

The study, published in Nature, revealed significant changes in gene regulation during critical developmental windows, particularly around the midpoint of pregnancy. During this period, neural stem cells transition from producing neurons to generating glial cells, while existing neurons mature and form synaptic connections.

According to Dr. Luo, "Neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development. Our map offers a baseline to compare against genetic studies of diseased-affected brains and pinpoint when and where molecular changes occur."

The findings have implications for improving stem cell-based models like brain organoids, offering a benchmark for accurately replicating human brain development. Additionally, the publicly available data resource could help scientists connect genetic variants associated with neuropsychiatric conditions to specific genes, cells, and developmental periods.

Dr. Paredes added, "Our study tackles the complex relationship between DNA organization and gene expression in developing human brain at ages typically not interrogated: the third trimester and infancy. The connections we’ve identified across different cell types through this work could untangle the current challenges in identifying meaningful genetic risk factors for neurodevelopmental and neuropsychiatric conditions.”