Biology subjects

Koreman, G. T.

Publications and source records attributed to Koreman, G. T..

6 recordsLinked to original sources

bioRxiv2026

The BAF complex works with FOS to regulate human neuronal activity-dependent ASD-associated gene programs

The BAF chromatin remodeling complex is critical to normal brain development, and rare variants within genes encoding BAF subunits are a common genetic cause of neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet the factors that direct BAF binding across the neuronal genome, the human neuronal gene programs that are regulated by BAF, and the mechanisms whereby BAF subunit perturbation leads to ASD are not known. We find that BAF binds with the activity-dependent transcription factor FOS to distal regulatory regions that, in response to neuronal activity, undergo chromatin opening and show evidence of enhancer activation. Knock-out of ARID1A, a BAF subunit implicated in ASD, leads to decreased chromatin accessibility at FOS/BAF binding sites concomitant with decreased expression of nearby activity-regulated ASD-associated genes. Additionally, we find that the FOS binding motif in FOS/BAF-bound regions is highly constrained in the human population, and that rare variants in this motif in ASD-affected individuals disrupt stimulus-dependent enhancer activation. This suggests that genetic variation in FOS/BAF-bound regions contributes to ASD pathogenesis, due to an inability to recruit FOS and BAF to enhancers to promote gene expression. Together, our findings highlight a role for BAF in mediating neuronal transcriptional programs downstream of FOS and reveal a mechanism by which non-coding variants may impact BAF function and contribute to risk for ASD.

neuroscience↗

bioRxiv2025

FOS binding sites are a hub for the evolution of activity-dependent gene regulatory programs in human neurons

After birth, sensory inputs to neurons trigger the induction of activity-dependent genes (ADGs) that mediate many aspects of neuronal maturation and plasticity. To identify human-specific ADGs, we characterized these genes in human-chimpanzee tetraploid neurons. We identified 235 ADGs that are differentially expressed between human and chimpanzee neurons and found that their nearby regulatory sites are species-biased in their binding of the transcription factor FOS. An assessment of these sites revealed that many are enriched for single nucleotide variants that promote or eliminate FOS binding in human neurons. Disrupting the function of individual species-biased FOS-bound enhancers diminishes expression of nearby genes and affects the firing dynamics of human neurons. Our findings indicate that FOS-bound enhancers are frequent sites of evolution and that they regulate human-specific ADGs that may contribute to the unusually protracted and complex process of postnatal human brain development.

evolutionary biology↗

bioRxiv2025

Human-chimpanzee tetraploid system defines mechanisms of species-specific neural gene regulation

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 human-chimpanzee tetraploid cells to distinguish gene expression changes due to cis-acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment. In neural progenitor cells, examination of both cis and trans changes -- combined with CRISPR inhibition and transcription factor motif analyses -- identified cis-acting, species-specific gene regulatory changes, including to TNIK, FOSL2, and MAZ, with widespread trans effects on neurogenesis-related gene programs. In excitatory neurons, we identified POU3F2 as a key cis-regulated gene with trans effects on synaptic gene expression and neuronal firing. This study identifies cis-acting genomic changes that cause cascading trans gene regulatory effects to contribute to human neural specializations, and provides a general framework for discovering genetic differences underlying human traits.

evolutionary biology↗

bioRxiv2023

A modular circuit architecture coordinates the diversification of courtship strategies in Drosophila

Identifying a mate is a central imperative for males of most species but poses the challenge of distinguishing a suitable partner from an array of potential male competitors or females of related species. Mate recognition systems are thus subject to strong selective pressures, driving the rapid coevolution of female sensory cues and male sensory preferences. Here we leverage the rapid evolution of female pheromones across the Drosophila genus to gain insight into how males coordinately adapt their detection and interpretation of these chemical cues to hone their mating strategies. While in some Drosophila species females produce unique pheromones that act to attract and arouse their conspecific males, the pheromones of most species are sexually monomorphic such that females possess no distinguishing chemosensory signatures that males can use for mate recognition. By comparing several close and distantly-related Drosophila species, we reveal that D. yakuba males have evolved the distinct ability to use a sexually-monomorphic pheromone, 7-tricosene (7-T), as an excitatory cue to promote courtship, a sensory innovation that enables D. yakuba males to court in the dark thereby expanding their reproductive opportunities. To gain insight into the neural adaptations that enable 7-T to act as an excitatory cue, we compared the functional properties of two key nodes within the pheromone circuits of D. yakuba and a subset of its closest relatives. We show that the instructive role of 7-T in D. yakuba arises from concurrent peripheral and central circuit changes: a distinct subpopulation of sensory neurons has acquired sensitivity to 7-T which in turn selectively signals to a distinct subset of P1 neurons in the central brain that trigger courtship behaviors. Such a modular circuit organization, in which different sensory inputs can independently couple to multiple parallel courtship control nodes, may facilitate the evolution of mate recognition systems by allowing males to take advantage of novel sensory modalities to become aroused. Together, our findings suggest how peripheral and central circuit adaptations can be flexibly linked to underlie the rapid evolution of mate recognition and courtship strategies across species.

neuroscience↗

bioRxiv2020

Upgraded CRISPR/Cas9 Tools for Tissue-Specific Mutagenesis in Drosophila

ABSTRACTCRISPR/Cas9 has emerged as a powerful technology for tissue-specific mutagenesis. However, tissue-specific CRISPR/Cas9 tools currently available in Drosophila remain deficient in three significant ways. First, many existing gRNAs are inefficient, such that further improvements of gRNA expression constructs are needed for more efficient and predictable mutagenesis in both somatic and germline tissues. Second, it has been difficult to label mutant cells in target tissues with current methods. Lastly, application of tissue-specific mutagenesis at present often relies on Gal4-driven Cas9, which hampers the flexibility and effectiveness of the system. Here we tackle these deficiencies by building upon our previous CRISPR-mediated tissue restricted mutagenesis (CRISPR-TRiM) tools. First, we significantly improved gRNA efficiency in somatic tissues by optimizing multiplexed gRNA design. Similarly, we also designed efficient dual-gRNA vectors for the germline. Second, we developed methods to positively and negatively label mutant cells in tissue-specific mutagenesis by incorporating co-CRISPR reporters into gRNA expression vectors. Lastly, we generated genetic reagents for convenient conversion of existing Gal4 drivers into tissue-specific Cas9 lines based on homology-assisted CRISPR knock-in (HACK). In this way, we expand the choices of Cas9 for CRISPR-TRiM analysis to broader tissues and developmental stages. Overall, our upgraded CRISPR/Cas9 tools make tissue-specific mutagenesis more versatile, reliable, and effective in Drosophila. These improvements may be also applied to other model systems.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2020

MAGIC: Mosaic Analysis by gRNA-Induced Crossing-over

Mosaic animals have provided the platform for many fundamental discoveries in developmental biology, cell biology, and other fields. Techniques to produce mosaic animals by mitotic recombination have been extensively developed in Drosophila melanogaster but are less common for other laboratory organisms. Here, we report mosaic analysis by gRNA-induced crossing-over (MAGIC), a new technique for generating mosaic animals based on DNA double-strand breaks produced by CRISPR/Cas9. MAGIC efficiently produces mosaic clones in both somatic tissues and the germline of Drosophila. Further, by developing a MAGIC toolkit for one chromosome arm, we demonstrate the method’s application in characterizing gene function in neural development and in generating fluorescently marked clones in wild-derived Drosophila strains. Eliminating the need to introduce recombinase-recognition sites in the genome, this simple and versatile system simplifies mosaic analysis in Drosophila and can be applied in any organism that is compatible with CRISPR/Cas9.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗