Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability
G. L. Boulting*, E. Durresi*, B. Ataman*, M. A. Sherman*, K. Mei, D. A. Harmin, A. C. Carter, D. R. Hochbaum, A. J. Granger, J. M. Engreitz, S. Hrvatin, M. R. Blanchard, M. G. Yang, E. C. Griffith, M. E. Greenberg
Nature Neuroscience (2021) DOI: 10.1038/s41593-020-00786-1

Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.

Nibbling 405 kb off the X: Viable deletion alleles eliminating 50 protein coding genes, including a chromatin factor involved in neuronal development
G. Minevich, A. Bernstein, K. Mei, R. J. Poole, O. Hobert
microPublication Biology (2019) DOI: 10.17912/micropub.biology.000187

Evolution of Osteocrin as an activity-regulated factor in the primate brain
B. Ataman*, G. L. Boulting*, D. A. Harmin, M. G. Yang, M. Baker-Salisbury, E.-L. Yap, A. N. Malik, K. Mei, A. A. Rubin, I. Spiegel, E. Durresi, N. Sharma, L. S. Hu, M. Pletikos, E. C. Griffith, J. N. Partlow, C. R. Stevens, M. Adli, M. Chahrour, N. Sestan, C. A. Walsh, V. K. Berezovskii, M. S. Livingstone, M. E. Greenberg
Nature 539(7628), 242-247. (2016) DOI: 10.1038/nature20111

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.