Combinatorial transcription factor activities on open chromatin induce embryonic heterogeneity in vertebrates

RIMLS researchers from the Faculty of Science Gert-Jan Veenstra and Simon van Heeringen, theme Cancer development and Immune defense, showed that transcription factors cooperate in a combinatorial fashion in generally open chromatin to orchestrate zygotic gene expression. This was recently published in the Embo Journal.

During vertebrate gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal‐ventral patterning and establishing of the dorsal axis. We applied single‐cell chromatin accessibility and transcriptome analyses to explore the emergence of cellular heterogeneity during gastrulation in Xenopus tropicalis. Transcriptionally inactive lineage‐restricted genes exhibit relatively open chromatin in animal caps, whereas chromatin accessibility in dorsal marginal zone cells more closely reflects transcriptional activity. We characterized single‐cell trajectories and identified head and trunk organizer cell clusters in early gastrulae. By integrating chromatin accessibility and transcriptome data, we inferred the activity of transcription factors in single‐cell clusters and tested the activity of organizer‐expressed transcription factors in animal caps, alone or in combination. The expression profile induced by a combination of Foxb1 and Eomes most closely resembles that observed in the head organizer. Genes induced by Eomes, Otx2, or the Irx3‐Otx2 combination are enriched for maternally regulated H3K4me3 modifications, whereas Lhx8‐induced genes are marked more frequently by zygotically controlled H3K4me3. Taken together, our results show that transcription factors cooperate in a combinatorial fashion in generally open chromatin to orchestrate zygotic gene expression.

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