Biology subjects

Bright, A. R.

Publications and source records attributed to Bright, A. R..

4 recordsLinked to original sources

bioRxiv2026

Stoichiometric transcription factor partnerships specify GABAergic neuron subtype identity

Combinatorial transcription factor (TF) codes specify neuronal fates, yet how quantitative differences in interacting TFs shape these decisions remains unresolved. We address this in the developing basal ganglia, where a pool of undifferentiated progenitors gives rise to both D1 and D2 medium spiny neurons (MSNs). Combining sparse in vivo CRISPR perturbation, lineage barcoding, and single-cell transcriptomics in mice, we find that loss of Sp9 shifts clonal fate bias from D2 toward D1 MSNs and intercalated cells. Mechanistically, chromatin profiling and biochemical assays show that at GC-rich promoters, SP9 binds DNA directly and activates transcription. At distal enhancers, SP9 binds indirectly, tethered by DLX factors, represses activity, and associates with the NuRD corepressor complex. The relative abundance of SP9 and DLX selects between these modes. These findings extend the combinatorial TF code beyond factor identity to relative proportions, with relevance to neurodevelopmental disorders.

developmental biology↗

bioRxiv2024

Nfib regulates progenitor competence in maturation of GABAergic neurons

Diverse types of GABAergic projection neurons and interneurons of the telencephalon derive from progenitors in a ventral germinal zone, called the ganglionic eminence. Using single-cell transcriptomics, chromatin accessibility profiling, lineage tracing, birthdating, heterochronic transplantation, and perturbation sequencing in mouse embryos, we investigated how progenitor competence influences the maturation and differentiation of these neurons. We found that the progression of neurogenesis over developmental time shapes maturation competence in ganglionic eminence progenitors, influencing how they progress into mature states. In contrast, differentiation competence, which defines the ability to produce diverse transcriptomic identities, remains largely unaffected by the stages of neurogenesis. Chromatin remodeling alongside a NFIB-driven regulatory gene module influences maturation competence in late-born neurons. These findings provide key insights into how transcriptional programs and chromatin accessibility govern neuronal maturation and the diversification of GABAergic neuron subtypes during neurodevelopment.

neuroscience↗

bioRxiv2020

Uncovering the mesendoderm gene regulatory network through multi-omic data integration

Mesendodermal specification is one of the earliest events in embryogenesis, where cells first acquire distinct identities. Cell differentiation is a highly regulated process that involves the function of numerous transcription factors (TFs) and signaling molecules, which can be described with gene regulatory networks (GRNs). Cell differentiation GRNs are difficult to build because existing mechanistic methods are low-throughput, and high-throughput methods tend to be non-mechanistic. Additionally, integrating highly dimensional data comprised of more than two data types is challenging. Here, we use linked self-organizing maps to combine ChIP-seq/ATAC-seq with temporal, spatial and perturbation RNA-seq data from Xenopus tropicalis mesendoderm development to build a high resolution genome scale mechanistic GRN. We recovered both known and previously unsuspected TF-DNA/TF-TF interactions and validated through reporter assays. Our analysis provides new insights into transcriptional regulation of early cell fate decisions and provides a general approach to building GRNs using highly-dimensional multi-omic data sets. HighlightsO_LIBuilt a generally applicable pipeline to creating GRNs using highly-dimensional multi-omic data sets C_LIO_LIPredicted new TF-DNA/TF-TF interactions during mesendoderm development C_LIO_LIGenerate the first genome scale GRN for vertebrate mesendoderm and expanded the core mesendodermal developmental network with high fidelity C_LIO_LIDeveloped a resource to visualize hundreds of RNA-seq and ChIP-seq data using 2D SOM metaclusters. C_LI

genomics↗

bioRxiv2020

Combinatorial action of transcription factors in open chromatin contributes to early cellular heterogeneity and organizer mesendoderm specification.

During gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal-ventral patterning and establishing of the dorsal axis. How transcription factors operate within the constraints of chromatin accessibility to mediate these processes is not well-understood. We applied chromatin accessibility and single cell transcriptome analyses to explore the emergence of heterogeneity and underlying gene-regulatory mechanisms during early gastrulation in Xenopus. ATAC-sequencing of pluripotent animal cap cells revealed a state of open chromatin of transcriptionally inactive lineage-restricted genes, whereas chromatin accessibility in dorsal marginal zone cells more closely reflected the transcriptional activity of genes. We characterized single cell trajectories in animal cap and dorsal marginal zone in early gastrula embryos, and inferred the activity of transcription factors in single cell clusters by integrating chromatin accessibility and single cell RNA-sequencing. We tested the activity of organizer-expressed transcription factors in mesoderm-competent animal cap cells and found combinatorial effects of these factors on organizer gene expression. In particular the combination of Foxb1 and Eomes induced a gene expression profile that mimicked those observed in head and trunk organizer single cell clusters. In addition, genes induced by Eomes, Otx2 or the Irx3-Otx2 combination, were enriched for promoters with maternally regulated H3K4me3 modifications, whereas promoters selectively induced by Lhx8 were marked more frequently by zygotically controlled H3K4me3. Our results show that combinatorial activity of zygotically expressed transcription factors acts on maternally-regulated accessible chromatin to induce organizer gene expression.

developmental biology↗