Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium
| Autor: | Jianqiang Ding, Pin-Xian Xu, Li Shen, Yong-Hwee E. Loh, Aarthi Ramakrishnan, Jun Li, Ting Zhang, Jinshu Xu, Bernd Fritzsch, Elaine Wong |
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| Rok vydání: | 2020 |
| Předmět: |
ATOH1
Fibroblast Growth Factor 8 AcademicSubjects/SCI00010 Biology Epithelium 03 medical and health sciences 0302 clinical medicine FGF8 Dual Specificity Phosphatase 6 Consensus Sequence Hair Cells Auditory Gene expression Genetics Humans Cell Lineage Nucleotide Motifs Enhancer Transcription factor Gene 030304 developmental biology Homeodomain Proteins Regulation of gene expression 0303 health sciences Genome Base Sequence Effector Gene regulation Chromatin and Epigenetics Cell Polarity Gene Expression Regulation Developmental Cell Differentiation DNA Cell biology Enhancer Elements Genetic Genetic Loci Multiprotein Complexes biology.protein 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | The transcription factor Six1 is essential for induction of sensory cell fate and formation of auditory sensory epithelium, but how it activates gene expression programs to generate distinct cell-types remains unknown. Here, we perform genome-wide characterization of Six1 binding at different stages of auditory sensory epithelium development and find that Six1-binding to cis-regulatory elements changes dramatically at cell-state transitions. Intriguingly, Six1 pre-occupies enhancers of cell-type-specific regulators and effectors before their expression. We demonstrate in-vivo cell-type-specific activity of Six1-bound novel enhancers of Pbx1, Fgf8, Dusp6, Vangl2, the hair-cell master regulator Atoh1 and a cascade of Atoh1’s downstream factors, including Pou4f3 and Gfi1. A subset of Six1-bound sites carry consensus-sequences for its downstream factors, including Atoh1, Gfi1, Pou4f3, Gata3 and Pbx1, all of which physically interact with Six1. Motif analysis identifies RFX/X-box as one of the most significantly enriched motifs in Six1-bound sites, and we demonstrate that Six1-RFX proteins cooperatively regulate gene expression through binding to SIX:RFX-motifs. Six1 targets a wide range of hair-bundle regulators and late Six1 deletion disrupts hair-bundle polarity. This study provides a mechanistic understanding of how Six1 cooperates with distinct cofactors in feedforward loops to control lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium. |
| Databáze: | OpenAIRE |
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