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

Abstract

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 profiles for ~90,000 cells spanning eleven 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, but also 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.

Integrated single-cell transcriptomic and epigenetic analyses of cell-state transition and lineage commitment in the embryonic mouse cerebellum

“…Among the top eight genes, Zic5, Zic2, Pax6, Hes5, Sox9, Lhx1, Sox2, and Pax3 , are well-known TFs important for cerebellar development. These observations suggest that key TFs acting in early cerebellar development are subjected to complex regulation via numerous CREs in agreement with a recent report 20 .…”

“…As expected, cell-type specific open chromatin regions are largely consistent with those identified by a recent snATAC- seq of mouse cerebella (Fig. S6F) 20 . Furthermore, the ATAC peaks specific for GABAergic progenitors are enriched for DNA sequenced bound by Ascl1 and Ptf1a 36 , whereas those specific for GCs and GCPs are enriched for sequenced bound by Atoh1 (Fig.…”

Integrated single-cell transcriptomic and epigenetic study of cell state transition and lineage commitment in embryonic mouse cerebellum

“…Powerful algorithms have been developed to harness time-series single-cell data to identify the molecular trajectories that describe cell fate specification in vertebrate embryogenesis (8)(9)(10). Although several studies using single-cell technology have examined the heterogeneous cell populations in the mouse (4,(11)(12)(13)(14)(15) and human cerebellum (16), systematic integrated RNA and ATAC analysis by sampling developing cerebellar cells is still lacking.…”

Epigenetics of alcohol-related liver diseases

“…These technologies also may help explain differences in presentation and outcome in patients at different points on the ARLD spectrum. [127][128][129] Response to injury and fate of various cell lineages are determined in part by sequence-specific transcription factors interacting with cis-regulatory elements in a cell-and tissue-dependent manner. This is a guiding principle to understanding heterogeneity in normal and diseased tissue.…”

“…These technologies may also help explain differences in presentation and outcome in patients at different points on the ARLD spectrum. [126] , [127] , [128] …”