Single cell epigenomic atlas of the developing human brain and organoids

Abstract

31Dynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as 32 fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. 33However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-34 cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing 35human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo 36 extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals 37 novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles 38 and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific 39 chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad 40 cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative 41 regulatory elements identified in homologous primary cell types. Together, our results reveal the important 42 contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and 43 provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical 44 development. 45 46Main text 47The diverse cell types of the human cerebral cortex (Fig. 1a) have been mostly classified based on a handful of 48 morphological, anatomical, and physiological features. Recent innovations in single cell genomics, such as single 49 cell mRNA sequencing (scRNA-seq), have enabled massively parallel profiling of thousands of molecular 50 features in every cell, uncovering the remarkable molecular diversity of cell types previously considered 51 homologous, such as excitatory neurons located in different areas of the cerebral cortex 1-6 . However, the 52 developmental mechanisms underlying the emergence of distinct cellular identities are largely unknown, as most 53 cortical neurons are generated at stages that are inaccessible to experimentation 5 . 54 55Over 60 years ago, Conrad Waddington introduced the concept of an epigenomic landscape to account for the 56 emergence of distinct cell fates 7 . In particular, chromatin state defines the functional architecture of the genome 57

Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders

“…However, cellular heterogeneity poses a significant challenge in addressing the complexity in the gene regulatory architecture of the human brain. The human brain is comprised of heterogeneous cell populations that encompass neurons and glia, which display distinct gene expression 3,[8][9][10] and chromatin accessibility profiles [11][12][13][14] . Higher-order chromatin interactions are crucial for linking these two units (genes and enhancers), because gene promoters often interact with distal regulatory elements 15,16 .…”

The Regulatory Evolution of the Primate Fine-Motor System

“…Recently, studies have begun to characterize the epigenomic properties of motor cortex in both rodents and primates (Adkins et al, 2020;Bakken et al, 2020;Li et al, 2020;Yao et al, 2020;Ziffra et al, 2020). However, none, to our knowledge, have attempted to explore differences within subdivisions of primary motor cortex that are associated with distinct behavioral phenotypes, and none have investigated the comparative regulatory genomic specializations of motor versus premotor cortical regions.…”

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

“…However, the ability of MPRAs to address clinically-relevant questions has, to date, largely been restricted by in vitro implementations, which can neither model the complex cell-type interactions of tissues-especially those of the brain-nor can they model tissues' full breadth of sex/developmental, environmental, or pharmacological complexity ( Figure 2). Critically, even the most complex in vitro models of brain tissue-organoids-lack almost 50% of cell type-specific accessible chromatin regions found in their in vivo counterpart (fetal brain) (75), suggesting that in vitro MPRAs alone cannot dissect functional variation in neuropsychiatry. As preclinical research tools, in vivo MPRAs would greatly expand the ability to assess regulatory activity in native cellular and physiologic contexts.…”