Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm

Jinshu Xu; Jun Li; Ting Zhang; Huihui Jiang; Aarthi Ramakrishnan; Bernd Fritzsch; Li Shen; Pin-Xian Xu

doi:10.1073/pnas.2025196118

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Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm

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Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm

Jinshu Xu, Jun Li, Ting Zhang, Huihui Jiang, Aarthi Ramakrishnan, Bernd Fritzsch, Li Shen and Pin-Xian Xu

Proceedings of the National Academy of Sciences - PNAS, Vol.118(12), p.1

03/23/2021

DOI: 10.1073/pnas.2025196118

PMCID: PMC8000026

PMID: 33723076

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Abstract

Specification of Sox2 proneurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that the Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce expression and promote proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of expression and lack of neurosensory identity, leading to abnormal apoptosis within the otic ectoderm. Brg1 binds to two of three distal 3' enhancers occupied by Six1, and Brg1-binding to these regions depends on Eya1-Six1 activity. We demonstrate that the activity of these enhancers in otic neurosensory cells specifically depends on binding to Six1. Furthermore, genome-wide and transcriptome profiling indicate that Brg1 may suppress apoptotic factor to inhibit apoptosis. Together, our findings reveal an essential role for Brg1, its downstream pathways, and their interactions with Six1/Eya1 in promoting proneurosensory fate induction in the otic ectoderm and subsequent neuronal lineage commitment and survival of otic cells.

otic neurosensory lineage

chromatin remodelers

transcription factors

Sox2 enhancers

regulation of otic Sox2 expression

Details

Title: Subtitle: Chromatin remodelers and lineage-specific factors interact to target enhancers to establish proneurosensory fate within otic ectoderm
Creators: Jinshu Xu - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Jun Li - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Ting Zhang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Huihui Jiang - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Aarthi Ramakrishnan - Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Bernd Fritzsch - Department of Otolaryngology, University of Iowa, Iowa City, IA 52242-1324
Li Shen - Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Pin-Xian Xu - Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.118(12), p.1
DOI: 10.1073/pnas.2025196118
PMID: 33723076
PMCID: PMC8000026
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: R01 AG060504 / NIA NIH HHS R01 DC014718 / NIDCD NIH HHS
Language: English
Date published: 03/23/2021
Academic Unit: Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984070328802771

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