By conducting tissue clearing and lightsheet imaging on intact brain samples from Chd8+/- mice and littermate controls, we were able to discover previously undocumented brain structural abnormalities and explain the cellular basis underlying macrocephaly caused by this mutation. These findings are described in our pre-print on bioRxiv.
Miguel and Sam win best talk/poster at Neuro/Genetics retreats
Congratulations to Miguel who won the best talk at the Neuroscience retreat for his work on advancing the maturation of human cortical organoids. Congratulations also to Sam for winning best poster for her work discovering chromatin interaction quantitative trait loci.
Ariana and Jason teaching at Cajal Course in Bordeaux
Ariana and Jason taught at the Cajal Course entitled Frontiers in Neural Organoid Modeling in Bordeaux, France.
Preprint on parallelized organoid imaging
We have demonstrated the utility of organoid imaging using a novel multi-camera array scanner that parallelizes imaging through the simultaneous use of 48 objective lenses and sensors, resulting in a 95% reduction in acquisition times compared to commercial high-content imagers. The microscope was built by our collaborator Roarke Horstmeyer’s lab at Duke. A preprint describing this microscope is found here.
Congrats to Drs. Felix Kyere and Ian Curtin
Felix and Ian successfully defended their dissertations describing new structural findings in Chd8 heterozygous loss of function mouse brains. Felix is staying on as a postdoc in the lab to finish up the project, and Ian took a postdoctoral fellowship at MIT. Congrats brothers in Chd8!
Molecular gene x treatment interactions relevant for autism
Our paper describing how genetic variation can alter molecular response to treatments, including valproic acid a known environmental factor where prenatal exposure increases the likelihood of an autism diagnosis, was published in Molecular Psychiatry. Here, we demonstrate gene x environment interactions that could accentuate or temper the effects of a known teratogen. This study design may be useful to find why some individuals are more susceptible than others to the impacts of environmental exposures.
Esther Park promoted to Research Assistant Professor
Congratulations to Esther Park, who was recently promoted to Research Assistant Professor in the Department of Genetics! Read more about the news here.
Organoid paper published in Cell Stem Cell
We published our first paper as part of the Infant Brain Imaging Study (IBIS) induced pluripotent stem cell (iPSC) project in Cell Stem Cell. We generated iPSCs from 18 participants in the infant brain imaging study who had longitudinal brain structural images acquired since infancy. Features from cortical organoids correlated with the brain growth of the individual from which they were derived. For example, gene expression at the crux of fate decisions between neural progenitor self renewal and neuronal differentiation were strongly associated with cortical surface area. Congrats to Rose Glass, Nana Matoba and all the wet, dry, and clinical labs that made such an ambitious project possible!
Jordan Valone Defends his Dissertation
Dr. Jordan Valone successfully defended his dissertation in Bioinformatics and Computational Biology! Jordan co-led our work on context-dependent genetic regulation and pharmacogenomics. Congratulations, Jordan!
Stein Lab at UNC Neuroscience Retreat
At the UNC Neuroscience Retreat, Jason gave an impromptu lecture on the interaction between bees and our most inspirational scientist, Dr. Nicholas Cage. And, he was more than honored to receive the “Mentor of the Year” award from the UNC Neuroscience Curriculum!
Stein lab at ASHG 2025
We attended the American Society of Human Genetics in Boston, where we had a lab reunion dinner! It was amazing to see everyone again.
Clear IT! Tissue Clearing Workshop at UNC
Together with colleagues from our sister university, the University of Tübingen in Germany, we organized a tissue clearing conference bringing experts from around the triangle to discuss new research in 3D image acquisition and analysis in April, 2025.
Preprint on molecular gene x treatment effects
We released a preprint on VPA and Li molecular quantitative trait loci in primary human neural progenitors. Gene by treatment (GxT) interactions are critical for understanding psychiatric disorder risk and variability in treatment response, yet their discovery remains challenging due to the complexity of human exposures. For example, while epidemiological birth cohorts demonstrated that valproic acid (VPA) taken during pregnancy strongly increases the likelihood of an autism spectrum disorder (ASD) diagnosis in the exposed child, only a small proportion of those exposed are affected with ASD. Similarly, while lithium has been successfully used as a treatment for bipolar disorder for over 75 years, around half of individuals treated have a beneficial clinical response. It is likely that genetic variation plays a strong role in response to each treatment, but pharmacogenomic studies are often underpowered and confounded by poorly controlled concentration, duration, and adherence of treatment. Here, we demonstrate a novel approach to dissect these interactions by investigating how common genetic variation alters gene regulatory responses to clinically relevant perturbations, which we call “GxT in a dish”, where the molecular response of each donor to well-controlled exposures can be precisely measured.
Jason is named a Yang Family Biomedical Scholar
Jason was named a Yang Family Biomedical Scholar by the UNC School of Medicine. Thank you to the Stein lab team over the years who have done such an amazing job discovering how genetics change human brain development and function that enabled this recognition. Thank you to the Department of Genetics and School of Medicine for nominating me. And, thank you to the Yang Family for funding our work! https://news.unchealthcare.org/2025/04/unc-school-of-medicine-names-2024-25-yang-family-biomedical-scholars/
Maya Yin joins the lab
We welcome Maya Yin, a graduate student in the Bioinformatics and Computational Biology program, to the lab!
Developmental Diversity in a Dish talk
You can watch a seminar on our recent work presented at the Developmental Diversity in a Dish seminar series, found here: https://www.youtube.com/playlist?list=PLbeFhDgIkXxd-3CLdfuWvGguZZOveIso4.
Continued domination at chili cookoff
For the second year in a row, the Stein lab has placed in the UNC Neuroscience Chili Cookoff. Jason placed 3rd as assessed by Chili Reviewers 1-3, and Ariana and Alvaro placed second in the People’s Choice Award. Here’s to some tasty chili.
Preprint on regulatory activity of cortical structure associated variants
We released a preprint on the regulatory activity of cortical structure associated variants. We conducted a multiplexed parallel reporter assay using common variants associated with inter-individual differences in the size of the human cortex. Most loci had a least one variant with regulatory potential, and a small subset of these loci showed Wnt-dependent activity. Those loci with regulatory activity were strongly enriched in Alu elements, a type of retrotransposon that has increased in prevalence along the human lineage together with brain size increases. These results help to explain the molecular mechanisms leading to differences in the structure of the human cortex. You can read more about our study here.
Preprint on organoid modeling of brain growth
We released a preprint describing organoid modeling of brain growth. Through a collaboration with the Infant Brain Imaging Study, we generated induced pluripotent stem cells (iPSCs) from 18 participants who had undergone longitudinal brain imaging during infancy. We differentiated these iPSCs into cortical organoids and studied how cellular and molecular processes occurring in these brain models in a dish recapitulate the brain growth of the individual from which they were derived. We found that gene expression levels within progenitor cells at the crux of fate decisions - deciding to become a neuron or another progenitor - were critical for determining inter individual differences in brain growth. These findings support the fidelity of cortical organoids as a model system. You can read more about our work here.
Context-dependent eQTL/caQTL paper published in Nature Neuroscience
Gene regulatory effects have been difficult to detect at many non-coding loci associated with brain-related traits, likely because some genetic variants have distinct functions in specific contexts. To explore context-dependent gene regulation, we measured chromatin accessibility and gene expression after activation of the canonical Wnt pathway in primary human neural progenitors. We identified many context-dependent genetic effects, some of which help explain the mechanisms underlying brain-related traits. This work was published in Nature Neuroscience.
