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

Jun Li; Ting Zhang; Aarthi Ramakrishnan; Bernd Fritzsch; Jinshu Xu; Elaine Y M Wong; Yong-Hwee Eddie Loh; Jianqiang Ding; Li Shen; Pin-Xian Xu

doi:10.1093/nar/gkaa012

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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

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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

Jun Li, Ting Zhang, Aarthi Ramakrishnan, Bernd Fritzsch, Jinshu Xu, Elaine Y M Wong, Yong-Hwee Eddie Loh, Jianqiang Ding, Li Shen and Pin-Xian Xu

Nucleic acids research, Vol.48(6), pp.2880-2896

04/06/2020

DOI: 10.1093/nar/gkaa012

PMCID: PMC7102962

PMID: 31956913

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Abstract

Abstract 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.

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Title: Subtitle: 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
Creators: Jun Li - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Ting Zhang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Aarthi Ramakrishnan - Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Bernd Fritzsch - Department of Biology, University of Iowa, Iowa, IA 52242-1324
Jinshu Xu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Elaine Y M Wong - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Yong-Hwee Eddie Loh - Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Jianqiang Ding - Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde 528308, Guangdong, China
Li Shen - Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Pin-Xian Xu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.48(6), pp.2880-2896
DOI: 10.1093/nar/gkaa012
PMID: 31956913
PMCID: PMC7102962
NLM abbreviation: Nucleic Acids Res
ISSN: 0305-1048
eISSN: 1362-4962
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1DC014718; DOI: 10.13039/100012636, name: NYSTEM, award: C029566
Language: English
Date published: 04/06/2020
Academic Unit: Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984070746602771

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