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Postdoc @bhadurilab.bsky.social Human brain development + single-cell omics

Huge thanks to Aparna + @BhaduriLab (esp Dan Jaklic, @Jalbsoto, @MilJessenya, Antoni Martija) & Brittney Wick + Maximilian Haeussler for hosting our perturb-seq data on UCSC Cell Browser! Excited to see how these can untangle more of the pathways shaping the human cortex 🧠(7/7).

Honored to join this amazing community 🎉

Follow-up experiments need a more accessible platform than human primary cortical tissues. So we benchmarked how PFC TFs operate in human cortical organoids. We id’d the PFC TF-to-Signature relationships that organoids can model – and those include the effects of YBX1 (4/7).

Across our perturbational datasets, we id’d PFC TF cohorts that work w/ YBX1 to shape the human PFC. We hypothesize that these overlapping regulatory relationships confer robustness on PFC fate specification while preserving sensitivity to extrinsic cues like retinoic acid (6/7).

Bulk & scRNA-seq has id’d 1000s of PFC marker genes, each enriched in the PFC in different cell types & time points. With our meta-module approach, we organized these markers into 18 spatiotemporally dynamic PFC signatures – tractable, molecular readouts of PFC patterning (2/7).

To find what controls these dynamic PFC signatures, we screened 35 PFC-enriched TFs in primary cultures from the developing human cortex. One standout: YBX1, a TF known to regulate neurogenesis, whose expression shows the strongest correlation with PFC signature activity (3/7).

🧵Excited to share our new preprint introducing iHOTT - an autologous tumor-immune co-culture model that captures patient-specific responses in #Glioblastoma 💥Now on @biorxivpreprint : biorxiv.org/content/10.1... Led by Dr. Shivani Baisiwala, Neurosurgery Resident in the lab

By knocking down YBX1 in organoids, we find that YBX1 is essential for PFC fate in a cell type specific manner – regulating transcription AND chromatin accessibility of PFC signatures in radial glia, while having a predominantly transcriptional role in deep layer neurons (5/7).

Live on bioRxiv🎉🧬🧠! We @BhaduriLab use perturb-seq in human cortical tissues to make sense of the shifting molecular trajectories that form the human prefrontal cortex. (1/7) www.biorxiv.org/content/10.6...

Excited to present our new preprint led by @claudianguyen95 uncovering how thalamic input shapes human cortical development! We discover that thalamic axons promote the generation of upper layer cortical neurons through NRXN1-mediated contacts with outer radial glia. www.biorxiv.org/content/10.1...

The cerebral cortex drives human cognition through the coordinated activity of discrete cortical areas, each harboring specialized molecular, structural and functional characteristics. Central to this organization is the prefrontal cortex (PFC), a hub for executive function that displays disproportionate expansion in humans and selective vulnerability to neurodevelopmental disorders. Previous work has identified a collection of PFC-enriched marker genes with dynamic expression trajectories, and re-analysis of these datasets converge these markers into 18 distinct molecular signatures of spatiotemporal PFC identity. However, the intrinsic gene networks that coordinate these molecular signatures to shape the human PFC remains unclear. Through pooled CRISPR activation screens in human primary cortical tissues, we have evaluated the ability of PFC-enriched transcription factors to intrinsically pattern PFC molecular identity. Our screens identify novel roles for the neurogenesis regulator, YBX1, in the activation of human PFC fate. In parallel screens and knock-down experiments in human cortical organoids, we define how YBX1 acts in concert with other PFC determinants to activate molecular signatures of PFC identity. Our findings support a model in which PFC patterning is orchestrated by cohorts of intrinsic determinants that initiate, potentiate, and modulate PFC gene signatures, conferring robustness to the development of the human PFC. ### Competing Interest Statement The authors have declared no competing interest. NIH, R00NS111731, R01MH132689, UM1MH130991, RF1MH132662, U24HG002371 Brain & Behavior Research Foundation, https://ror.org/03a63f080, Young Investigator Award Alfred P. Sloan Foundation, https://ror.org/052csg198, Sloan Fellowship Rose Hills Foundation, Innovation Award Esther A. & Joseph Klingenstein Fund, Klingenstein-Simons Fellowship Simons Foundation, https://ror.org/01cmst727, Klingenstein-Simons Fellowship Ablon Trust, Ablon Scholar Award Department of Biological Chemistry, UCLA Zamenhof Scholarship UCLA Eli and Edythe Broad Center of Regenerative Medicine, Innovation Award, Stem Cell Research Training Program University of California, Los Angeles, https://ror.org/046rm7j60, Eugene V. Cota-Robles Award California Institute for Regenerative Medicine, https://ror.org/033m8b439, DISC0-14514, DISC4-16337 National Science Foundation, Graduate Research Fellowship Program