An analytical pipeline called Iteratively Defined Lengths of Inaccessibility (IDLI) maps the genome-wide occupancy of a range of nucleosome types and shows that most nucleosomes exhibit programmed ‘di...

The developing human cortex is composed of diverse cell types, but how nutrient metabolism shapes their fate has remained unclear. This study maps the metabolic landscape of the developing human corte...

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

Dr. Aparna Bhaduri, assistant professor of medicine and biological chemistry at the David Geffen School of Medicine at UCLA, has been named a recipient of the 2026 Pershing Square Sohn Cancer Prize, a...

An analytical pipeline called Iteratively Defined Lengths of Inaccessibility (IDLI) maps the genome-wide occupancy of a range of nucleosome types and shows that most nucleosomes exhibit programmed ‘di...

An analytical pipeline called Iteratively Defined Lengths of Inaccessibility (IDLI) maps the genome-wide occupancy of a range of nucleosome types and shows that most nucleosomes exhibit programmed ‘di...

Colonic stem cells retain a memory of inflammation following disease resolution and there is a mechanistic link between chronic inflammation and malignancy, suggesting potential strategies to mitigate...

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Ge and Kan et al. develop and benchmark a human organoid tumor transplantation (HOTT) system to uncover how microenvironmental cues influence glioblastoma states. They identify a non-catalytic role for microenvironmental PTPRZ1 in driving mesenchymal programs and extending tumor microtubes in patient tumor cells.

Baisiwala et al. introduce iHOTT, an autologous organoid co-culture system that preserves human tumor-immune interactions and T cell clonal responses. iHOTT mirrors clinical responses to PD-1 blockade and provides a platform for evaluating personalized immunotherapy strategies in glioblastoma.

CRISPR screens in iPSC-derived neurons reveal that the E3 ubiquitin ligase CRL5SOCS4 ubiquitinates tau, that CUL5 expression is correlated with resilience in human Alzheimer’s disease, and that electr...

Systematic screening of transcription factors reveals conserved mechanisms governing cortical radial glia lineage progression across primates and provides a framework for functional dissecti...

An analysis of cell-type diversity in brain samples from a variety of mammalian species, both during development and in adult animals, reveals that the TAC3 initial class of striatal interneurons is c...

Mutations in the chromatin reader and tumor suppressor ZMYND11 are the cause of ZMYND11-related syndromic intellectual disability (ZRSID), a disorder characterized by symptoms such as language and mot...

Adenosine triphosphate (ATP)–dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remod...

DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...

Tissue-resident macrophages (TRMs) are innate immune cells that participate in tissue development, homeostasis, and immune surveillance. Extensive efforts have been made to recapitulate TRM developmen...

According to the protocortex hypothesis, extrinsic thalamic signaling is necessary for refining cortical areas and cell types, but the mechanism by which these inputs shape the development and expansi...

A major challenge in human evolutionary biology is to pinpoint genetic differences that underlie human-specific traits, such as increased neuron number and differences in cognitive behaviors. We used ...

Characterization of cell type emergence during human cortical development, which enables unique human cognition, has focused primarily on anatomical and transcriptional characterizations. Metabolic pr...

Pluripotent stem cells are susceptible to acquiring detrimental epigenetic abnormalities, posing a hurdle to their safe use in biomedical applications. Using pluripotent cells with defined genetic backgrounds, Stadtfeld and colleagues show that genetic variation is a major driver of epigenome stability and identify candidate regulators. These findings will enable novel approaches to stabilize the epigenome of pluripotent cells in culture.

Using a 3D co-culture system of iPSC-derived neurons and glia, termed iAssembloids, combined with CRISPRi-based screening, Li et al. investigate the effect of glial cells on neuronal activity and surv...

Natural selection has shaped the gene regulatory networks that orchestrate the development of the neocortex, leading to diverse neocortical structure and function across mammals, but the molecular and...