Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells

Abstract

Spatially distinct gene expression profiles in neural stem cells (NSCs) are a prerequisite to the formation of neuronal diversity, but how these arise from the regulatory interactions between chromatin accessibility and transcription factor activity has remained unclear. Here, we demonstrate that, despite their distinct gene expression profiles, NSCs of the mouse cortex and spinal cord share the majority of their DNase I hypersensitive sites (DHSs). Regardless of this similarity, domain-specific gene expression is highly correlated with the relative accessibility of associated DHSs, as determined by sequence read density. Notably, the binding pattern of the general NSC transcription factor SOX2 is also largely cell type specific and coincides with an enrichment of LHX2 motifs in the cortex and HOXA9 motifs in the spinal cord. Interestingly, in a zebrafish reporter gene system, these motifs were critical determinants of patterned gene expression along the rostral-caudal axis. Our findings establish a predictive model for patterned NSC gene expression, whereby domain-specific expression of LHX2 and HOX proteins act on their target motifs within commonly accessible cis-regulatory regions to specify SOX2 binding. In turn, this binding correlates strongly with these DHSs relative accessibility-a robust predictor of neighboring gene expression.

Inference of cell type specific regulatory networks on mammalian lineages

“…A straightforward way to combine information across multiple cell types is clustering and dimensionality reduction [36, 39, 41, 42, 44, 48, 50, 102]. Such approaches can be used to group cell types based on their genome-wide profiles or group genomic loci based on their signal across multiple cell types.…”

“…These approaches model expression level or change in expression as a function of features capturing the chromatin state, TF occupancy, and sequence composition in proximal and distal regions [40, 42, 107]. These approaches differ in whether they predict change in expression level (e.g., [42, 107]) or differential expression status for a gene [40], as well as how they handle distal elements. For example, Gonzalez et al [107] initially assign distal regions to the nearest gene followed by reassignment based on prediction error, whereas Hagey et al [42] assign a distal region to all genes within a 500kb window.…”

“…These approaches differ in whether they predict change in expression level (e.g., [42, 107]) or differential expression status for a gene [40], as well as how they handle distal elements. For example, Gonzalez et al [107] initially assign distal regions to the nearest gene followed by reassignment based on prediction error, whereas Hagey et al [42] assign a distal region to all genes within a 500kb window. In all cases, a linear or logistic regression model learns feature weights, which can identify important cis -regulatory elements for cell type specific expression.…”

Pioneer transcription factors shape the epigenetic landscape

“…Indeed, pioneers show different binding repertoires in different cell types. For example, Sox2 binds different target subsets in mouse cortex and spinal cord (67), indicating that there are additional constraints on pioneer binding. Further, the pluripotency factors OSK have a large subset of targets that only become accessible in the late phase of reprograming towards iPS (21).…”

Epigenomic Landscapes of hESC-Derived Neural Rosettes: Modeling Neural Tube Formation and Diseases

“…Both factors are known to co-localized with Sox2 during early neurodevelopment in mice and are critical determinants of regional-specific Sox2 occupancy. For example, Lhx2 is more enriched in rostral regions (anterior fate) and HoxA9 is more enriched in caudal regions (posterior fate) (Hagey et al, 2016). While SOX2 and LHX2 genes are highly expressed in NRs, HOXA9 was not detected in NRs.…”