Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells

doi:10.1126/science.abg4696

GSTDTAP > 气候变化

DOI	10.1126/science.abg4696
	Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells
	Ioannis Sarropoulos; Mari Sepp; Robert Frömel; Kevin Leiss; Nils Trost; Evgeny Leushkin; Konstantin Okonechnikov; Piyush Joshi; Peter Giere; Lena M. Kutscher; Margarida Cardoso-Moreira; Stefan M. Pfister; Henrik Kaessmann
	2021-08-27
发表期刊	Science
出版年	2021
英文摘要	Gene-regulatory networks govern the development of organs. Sarropoulos et al. analyzed mouse cerebellar development in the context of gene-regulatory networks. Single nuclear profiles analyzing chromatin accessibility in about 90,000 cells revealed diversity in progenitor cells and genetic programs guiding cellular differentiation. The footsteps of evolution were apparent in varying constraints on different cell types. Science , abg4696, this issue p. [eabg4696][1] ### INTRODUCTION The cerebellum contributes to many complex brain functions, including motor control, language, and memory. During development, distinct neural cells are generated at cerebellar germinal zones in a spatiotemporally restricted manner. Cis-regulatory elements (CREs), such as enhancers and promoters, and the transcription factors that bind to them are central to cell fate specification and differentiation. Although most CREs undergo rapid turnover during evolution, a few are conserved across vertebrates. ### RATIONALE Bulk measurements of CRE activity have provided insights into gene regulation in the cerebellum, as well as into the evolutionary dynamics of CREs during organ development. However, they lack the cellular resolution required to assess cell-type differences in regulatory constraint and unravel the regulatory programs associated with the specification and differentiation of cell types. ### RESULTS Here, we generated a single-cell atlas of gene regulation in the mouse cerebellum spanning 11 developmental stages, from the beginning of neurogenesis to adulthood. By acquiring snATAC-seq (single-nucleus assay for transposase accessible chromatin using sequencing) profiles for ~90,000 cells, we mapped all major cerebellar cell types and identified candidate CREs. Characterization of CRE activity across the cerebellum development highlights the cell- and time-specificity of gene regulation. Many of the differentially accessible CREs are specific to a single cell type and state, but we also identified a fraction of CREs with pleiotropic (shared) activity. At early developmental stages, temporal changes in CRE activity are shared between progenitor cells from different germinal zones, supporting a model of cell fate induction through common temporal cues. Pleiotropic CREs in major cerebellar neuron types (granule cells, Purkinje cells, and inhibitory interneurons) are more active at early differentiation states, and the regulatory programs gradually diverge as differentiation proceeds. Based on comparisons to vertebrate genomes, we observed a decrease in CRE sequence conservation during development for all cerebellar cell types, a pattern that is largely explained by differentiation as well as by additional temporal differences between cells from matched differentiation states. Across cell types, differences in regulatory conservation are most pronounced in the adult, where microglia—the immune cells of the brain—show the fastest evolutionary turnover. By contrast, mature astrocytes harbor the most conserved intergenic CREs, not only in the cerebellum but also across a wide range of cell types in adult mouse organs. To evaluate the conservation of CRE activity, we acquired snATAC-seq profiles for ~20,000 cerebellar cells from the gray short-tailed opossum, a marsupial separated from mouse by ~160 million years of evolution. Our comparative analysis of CRE activity in the two therian species reinforced our sequence-based conclusions regarding differences in CRE constraint across cell types and developmental stages and also revealed that despite the overall high turnover of CREs, radical repurposing of spatiotemporal CRE activity is rare, at least between cell types in the same tissue. ### CONCLUSION This study reveals extensive temporal differences in CRE activity across cerebellar cell types and a shared decrease in CRE conservation during development and differentiation. Given that the cerebellum has been successfully used as a model system to study cell fate specification, neurogenesis, and other developmental processes, we expect that our observations regarding the developmental and evolutionary dynamics of regulatory elements, and their interplay, are also applicable to mammalian organs in general. ![Figure][2] Cis-regulatory elements in cerebellar cells. snATAC-seq delineates cell- and time-specific CRE activity in the developing mouse cerebellum (left). The chromatin accessibility profiles of cerebellar neuron types gradually diverge during differentiation as the activity of pleiotropic (shared) CREs decreases (top right). The evolutionary conservation of CRE sequences in vertebrates and activity in therian mammals decreases across development and differs between cell types (bottom right). mRNA, messenger RNA; PCA, principal components analysis; TF, transcription factor. Organ development is orchestrated by cell- and time-specific gene regulatory networks. In this study, we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring snATAC-seq (single-nucleus assay for transposase accessible chromatin using sequencing) profiles for ~90,000 cells spanning 11 stages, we mapped cerebellar cell types and identified candidate cis - regulatory elements (CREs). We detected extensive spatiotemporal heterogeneity among progenitor cells and a gradual divergence in the regulatory programs of cerebellar neurons during differentiation. Comparisons to vertebrate genomes and snATAC-seq profiles for ∼20,000 cerebellar cells from the marsupial opossum revealed a shared decrease in CRE conservation during development and differentiation as well as differences in constraint between cell types. Our work delineates the developmental and evolutionary dynamics of gene regulation in cerebellar cells and provides insights into mammalian organ development. [1]: /lookup/doi/10.1126/science.abg4696 [2]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/336655
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Ioannis Sarropoulos,Mari Sepp,Robert Frömel,et al. Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells[J]. Science,2021.
APA	Ioannis Sarropoulos.,Mari Sepp.,Robert Frömel.,Kevin Leiss.,Nils Trost.,...&Henrik Kaessmann.(2021).Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells.Science.
MLA	Ioannis Sarropoulos,et al."Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells".Science (2021).