Biology subjects

Harmin, D. A.

Publications and source records attributed to Harmin, D. A..

3 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↗

bioRxiv2021

Modeling autism-associated SHANK3 deficiency using human cortico-striatal organoids generated from single neural rosettes

Our understanding of the human brain is limited by the lack of experimental models to mechanistically probe the properties of brain cells at different developmental stages under normal and pathological conditions. We developed a new method for generating human cortico-striatal organoids from stem cell-derived single neural rosettes (SNRs) and used it to investigate cortico-striatal development and deficits caused by the deficiency of an autism- and intellectual disability-associated gene SHANK3. We show that SNR-derived organoids consist of different cortico-striatal cells, including pallial and subpallial progenitors, primary cortical and striatal neurons, interneurons, as well as macroglial and mural cells. We also demonstrate that neurons in SNR-derived organoids are predictably organized, functionally mature, and capable of establishing functional neural networks. Interestingly, we found that the cellular and electrophysiological deficits in SHANK3-deficient SNR-derived organoids are dependent on the level of SHANK3 expression and that organoids with complete hemizygous SHANK3 deletion have disrupted expression of several clustered protocadherins and multiple primate-specific zinc-finger genes. Together, this study describes a new method for using SNRs to generate organoids, provides new insights into the cell lineages associated with human cortico-striatal development, and identifies specific molecular pathways disrupted by hemizygous SHANK3 deletion, which is the most common genetic abnormality detected in patients with 22q13 deletion syndrome.

neuroscience↗

bioRxiv2018

Epigenomic Profiling and Single-Nucleus-RNA-Seq Reveal Cis-Regulatory Elements in Human Retina, Macula and RPE and Non-Coding Genetic Variation.

Cis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS. We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive resource of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.

neuroscience↗