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.

IDDRC organoid cross-site reproducibility project published in Stem Cell Reports

We evaluated the level of reproducibility of organoid differentiation using the same iPSC line differentiated multiple times across 3 different sites. Cell type proportions and cortical wall organization were reproducible, but metabolic gene expression levels as well as size did exhibit variability across sites. We hope this will inspire cross-site meta-analyses to increase sample sizes in iPSC-derived organoid studies. You can read more about our work here.

Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis published in AJHG

There are many types of gene regulation occurring in the human genome that tune not just the level of expression of a gene, but also RNA editing and alternative polyadenylation. These forms of gene regulation are poorly studied during human development. Here, we show that RNA editing and polyadenylation are highly cell type specific, and that genetic variation impacts these post-transcriptional modifications. Our work was published in the American Journal of Human Genetics.

Context dependent genetic variant effects revealed through Wnt stimulation

Nana Matoba, Bran Le, and Jordan Valone released a preprint describing context dependent genetic variant effects. Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits. The study can be found here.

Cell type specific genetic effects on post transcriptional modifications

Nil Aygün led a study on identifying genetic variants affecting RNA editing and alternative polyadenylation sites in human neural progenitors and their differentiated neuronal progeny. More RNA-editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL in CCDC88A with educational attainment and a progenitor apaQTL in EP300 with schizophrenia, suggesting genetically mediated post-transcriptional regulation during brain development lead to differences in brain function. The study can be found here.

Cross-site reproducibility of cortical organoid differentiation

Rose Glass together with Elisa Waxman and Deb French at CHOP, and Satoshi Yamashita and Kazue Hashimoto-Torii at Children’s National released a preprint evaluating the reproducibility or cortical organoid differentiation. Cell type proportions were found to be largely reproducible across sites, but differences in gene expression were identified. The study can be found here.

Brandon Le successfully defends his dissertation

Brandon Le successfully defended his dissertation on stimulus specific genetic effects in human neural progenitor cells. He is now finishing up this work as a postdoc in the Stein lab. Congrats Bran!

Dr. Rose Glass successfully defends her dissertation

Rose successfully defended her dissertation on evaluating the reproducibility of human cortical organoids as well as using organoids to model brain overgrowth in autism. She is now a postdoc with Mustafa Sahin at Boston Children’s Hospital. Congrats Rose!

Talk on Drug Discovery News

Jason gave a recorded webinar for the Drug Discovery News website on a recent paper describing a “pharmacogenomics in a dish” approach that we applied. You can see the talk here.