Mapping Transcription Factors in the Brain Transcription factors (TFs) are proteins
Positive Parasites Parasites are typically seen as harmful, but what if they could be used for good? One of the biggest challenges in treating neurological conditions is that medications often can't cross the blood-brain barrier, a protective
that help regulate gene expression. By binding to specific regions of DNA, TFs either activate or suppress RNA production. These proteins are involved in nearly every biological process, from organ development and cell differen- tiation to responses to environmental changes. Given their central role, disruptions in TF function can lead to various diseases, including neuropsychiatric disorders. Understanding how TFs work in the brain has been challenging due to the complexity and limited access to brain tissue. To address this gap, researchers conducted a groundbreaking study map- ping TF activity in human brain tissues. Using advanced genomic techniques like ChIP-seq, RNA-seq, ATAC-seq, and DNA methylation profiling, they analyzed tissue from four postmortem brain donors. This work involved over 1,000 experiments and focused on specific brain regions and cell types, such as neurons and glial cells.
shield that limits access to the brain. However, Toxoplasma gondii , a single-celled parasite transmitted through raw meat and unwashed fruits and vegetables, has no trouble infiltrating the brain. This parasite is surprisingly common in nature—many cat owners carry a latent T. gondii infection from handling cat litter. For most people, the infection causes no harm. However, pregnant women need to avoid exposure to the parasite, as it can seriously harm the developing fetus. Because T. gondii can naturally cross the blood-brain barrier, scientists are investigating whether it can be used to deliver protein treatments to brain cells. In a recent study, researchers engineered T. gondii to carry therapeutic proteins attached to two secretory organelles: the rhoptry and dense granules.
T. gondii infection
silencer TFs
activator TFs
repressor TFs
Fecal Oocysts
Tissue cysts
The study identified over 200,000 genomic regions where TFs bind to DNA, many of which display cell-type-specific activity. TFs like TBR1 and SATB2 were identified as key regulators of gene expression in neurons.
attractor TFs
Researchers also discovered high-occupancy target (HOT) sites—regions where multiple TFs bind— unique to brain tissue, which had not been observed in previous studies using cell lines. These findings link specific TF activities to neuropsychiatric disorders, emphasizing the importance of studying TF function in actual brain tissues. This extensive dataset is a valuable resource for researchers investigating gene regulation in the brain. It opens the door to a better understanding of how
The rhoptry uses a “kiss-and-spit” method to inject proteins into brain cells, while the dense granules release proteins once inside the cells. This dual approach allowed the parasite to deliver two different proteins simultaneously. The research showed that T. gondii successfully delivered proteins to both mouse and human brain cells in the lab, as well as to living mice. While much more research is needed before this method can be used to treat human diseases—such as creating safe versions of T. gondii —the study represents a promising new avenue for treating brain conditions that are difficult to reach with traditional therapies. It’s a fascinating example of how one disease pathway might help tackle another, offering hope for new treatments for brain diseases. n REFERENCE: Bracha, S., et al. Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons. Nat Microbiol [2024] 9, 2051–2072. https://doi.org/10.1038/s41564-024-01750-6
enhancer TFs
REFERENCE: Loupe J.M., et al. Multiomic profiling of transcription factor binding and function in human brain. Nature Neuroscience [2024] 27(7):1387-1399. https://doi.org/10.1038/s41593-024-01658-8 transcription factors influence brain function and their potential roles in mental health disorders, paving the way for new discoveries in neuroscience and medicine. n
The laboratory of HudsonAlpha faculty researcher Richard Myers, PhD, contributed to this work.
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