Temporal analysis of enhancers during mouse cerebellar development reveals dynamic and novel regulatory functions

Abstract

We have identified active enhancers in the mouse cerebellum at embryonic and postnatal stages which provides a view of novel enhancers active during cerebellar development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Furthermore, by comparing our data with relevant brain development ENCODE histone profiles and cerebellar single-cell datasets we have been able to generalize and expand on the presented analyses, respectively. We have made the results of our analyses available online in the Developing Mouse Cerebellum Enhancer Atlas (https://goldowitzlab.shinyapps.io/developing_mouse_cerebellum_enhancer_atlas/), where our dataset can be efficiently queried, curated and exported by the scientific community to facilitate future research efforts. Our study provides a valuable resource for studying the dynamics of gene expression regulation by enhancers in the developing cerebellum and delivers a rich dataset of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.

Early-life stress alters postnatal chromatin development in the nucleus accumbens

“…Among non-activated cells, chromatin accessibility largely increased into adulthood, with 219 regions closing and 609 regions opening ( Supplemental Figure 2A ). This is consistent with earlier work showing that overall more enhancers become activated than repressed across later stages of postnatal development (Stroud et al, 2020; Ramirez et al, 2022).…”

Generation of an enhancer-driven gene expression viral tool specific to dentate granule cell-types through direct hippocampal injection

“…We also studied the expression patterns at early post-natal stages, since age can highly influence enhancer activity due to variations in genetic regulation throughout development ( Ma and Zhang, 2020 ; Zhang et al, 2022 ). During initial developmental phases there are massive changes in neuronal architecture, which is also reflected in the transcriptional regulation of gene expression ( Mason et al, 2012 ; Harabula and Pombo, 2021 ; Janssen and Lorincz, 2022 ; Ramirez et al, 2022 ; Shirane, 2022 ). It is therefore important to assess enhancer expression patterns in animal of different ages.…”

Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7

“…For example, MIXL1 is a key player in Wnt/TGF-β signaling in the early mesodermal differentiation of hESCs [ 30 , 31 ]. BHLHE22 is a novel regulator that can direct neural circuit assembly in part through precise regulation [ 32 , 33 ]. Previous studies have confirmed that LHX1 originates from the endoderm and plays an important role in development [ 34 , 35 ], and NKX2 genes are primarily expressed in the mesendoderm-derived organs, such as the heart and gut[ 36 ].…”