Multi-omic profiling of the developing human cerebral cortex at the single cell level

Abstract

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements. We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across 6 broad developmental time-points from fetus to adult. We identified cell-type specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at cis-regulatory elements precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell-type and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination, serve as a developmental blueprint of the human brain and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.One-Sentence SummarySimultaneous profiling of gene expression and chromatin accessibility in single nuclei from 6 developmental time-points sheds light on cell fate determination in the human cerebral cortex and on the molecular basis of neuropsychiatric disease.

Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome

“…To estimate the cell composition in the sorted cells, we used single cell references of adult ( 25 ) and developing brains ( 26 ) with dtangle ( 27 ) to perform deconvolution analysis. Briefly, we first regressed out the selected covariates as described above.…”

Multimodal single-cell sequencing of the human cortex reveals neuronal vulnerability and activated glial cell states in focal cortical dysplasia

“…The majority of single-cell studies so far have focused on a single modality such as RNA or ATAC sequencing, and a few studies have analyzed the human brain from a multi-omics perspective 16,33 . Paired single-cell studies, which generate multiple readouts from the same cell, are still in their infancy due to technical limitations and cost.…”

Recruitment of Homodimeric Proneural Factors by Conserved CAT-CAT E-Boxes Drives Major Epigenetic Reconfiguration in Cortical Neurogenesis

“…Several studies highlighted specific proneural factors or E-proteins upon finding enrichment in their associated motifs as described in motif databases such as JASPAR. These enrichments have been interpreted multiple times as evidence of the action of the associated factor, and consequently possibly misled experimental designs for further functional assays, inducing or repressing the expression of these factors 33,45,50 . We propose that motif archetypes as the ones obtained by Vierstra et al 61 should be used instead, and complemented, when possible, by the assessment of the correlation between the expression of the transcription factors and the accessibility of the motifs, narrowing down the list of putative candidates, as in Trevino et al 2021 44 .…”