Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability

Abstract

Neuronal activity-dependent gene expression is essential for brain development. While transcriptional and epigenetic effects of neuronal activity have been explored in the mouse, such an investigation is lacking in human. 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 (hiPSC)-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible following 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.

Developmental Dynamics of RNA Translation in the Human Brain

“…Heritability enrichment analysis was performed using stratified linkage disequilibrium score regression (LDSC) 62 as described in Boulting et al. 52 Briefly, we obtained a baseline model of 54 annotations from Finucane et al and augmented the model with three human brain-specific regulatory annotations from Rizzardi et al. 63 We then tested heritability enrichment of neurological and non-neurological diseases for annotations defined from sORFs from 3 categories: all sORFs in the human brain or NGN2-derived neurons, all sORFs in the human heart 4 , and any sORF translated from an activity-dependent RNA.…”

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

“…In agreement with CRTC1’s role in the induction of these neuroplasticity genes, accumulating evidence supports its involvement in neuronal plasticity processes, such as activity- and BDNF-induced dendritic growth of developing cortical neurons ( Li et al, 2009 ; Finsterwald et al, 2010 ), maintenance of hippocampal late-phase LTP ( Zhou et al, 2006 ; Kovacs et al, 2007 ; Uchida et al, 2017 ), and long-term memory formation ( Sekeres et al, 2012 ; Nonaka et al, 2014 ; Parra-Damas et al, 2014 , 2017a ; Uchida et al, 2017 ; Zhang et al, 2019 ; Shu et al, 2020 ; Yan et al, 2021 ). Of particular importance, increasing evidence suggests that CRTC1 dysregulation may be implicated in the etiopathogenesis of neurodegenerative diseases, such as Huntington’s, Parkinson’s, and Alzheimer’s disease, as well as psychiatric disorders ( Boulting et al, 2021 ), including mood disorders [reviewed in Saura and Cardinaux (2017) ].…”

Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin

“…Murinae-specific open chromatin, and human candidate enhancers activated during neuron activity [95] are enriched for overlapping clusters with predicted Euarchonta-specific gains or Muroidea-specific losses of open chromatin, suggesting that there may be Muroidea-specific enhancer signatures of Muroidea neuron activity. Although no study, to our knowledge, has evaluated this for large numbers of species, a few studies have compared neuron activity between mice and one or two Euarchonta and found striking differences, including lower spiking frequencies in fast-spiking mouse cortical neurons relative to human and rhesus macaque [99] and lack of expression of h-Channels in mouse excitatory neurons relative to human [100].…”

“…For the mouse neuron firing candidate enhancers, we used the regions in Tables 11, S12 and S13 from a recent study of enhancers activated during mouse neuron firing [94] and used liftOver [111] to map the coordinates from mm9 to mm10. For the human GABAergic neuron activity candidate enhancers, we used the regions in Supp Data 12 from a recent study of enhancers activated during human neuron activation [95] and used liftOver to map the coordinates from hg19 to hg38 [111]. For the mouse liver regeneration candidate enhancers, we used various subsets of regions from Supplemental Table 1 from a recent study of enhancers activated during liver regeneration [96]; for each category of regions in Supplemental Table 19, we required the FDR to be less than 0.05 and the log2 fold-change to be greater than 1 (for ) or less than 1 (for ).…”

“…and each brain cluster that was open in human overlapped human candidate enhancers associated with neuron activity[95] more than expected by chance (Supplemental…”