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Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells

View ORCID ProfileCristina Zibetti, Sheng Liu, Jun Wan, Jiang Qian, View ORCID ProfileSeth Blackshaw
doi: https://doi.org/10.1101/238279
Cristina Zibetti
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
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  • ORCID record for Cristina Zibetti
Sheng Liu
2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
6Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN 46202
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Jun Wan
2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
6Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN 46202
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Jiang Qian
2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
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  • For correspondence: sblack@jhmi.edu jiang.qian@jhmi.edu
Seth Blackshaw
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
4Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
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  • For correspondence: sblack@jhmi.edu jiang.qian@jhmi.edu
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Abstract

Retinal progenitor cells (RPCs) pass through multiple stages of developmental competence, where they successively acquire and lose the ability to generate individual cell subtypes. To identify the transcriptional regulatory networks that control these transitions, we conducted epigenomic and transcriptomic profiling of early and late-stage RPCs and observed a developmentally dynamic landscape of chromatin accessibility. Open chromatin regions that showed stage-specificity, as well as those shared by early and late-stage RPCs, were selectively targeted by the homeodomain factor Lhx2, which is expressed throughout retinal neurogenesis but also regulates many stage-specific processes in RPCs. Stage-specific Lhx2 binding sites were frequently associated with target sites for transcription factors that are preferentially expressed in either early or late-stage RPCs, and which were predicted to possess pioneer activity. Lhx2 loss of function in RPCs led to a loss of chromatin accessibility at both direct Lhx2 target sites and more broadly across the genome, as well as a loss of binding by transcription factors associated with stage-specific Lhx2 target sites. These findings demonstrate a central role for Lhx2 in control of chromatin accessibility in RPCs, and identify transcription factors that may guide stage-specific target site selection by Lhx2.

Summary Lhx2 is a central regulator of chromatin accessibility in retinal progenitor cells, and interacts with stage-specific transcription factors to regulate genes that are dynamically expressed during retinal neurogenesis.

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Posted December 23, 2017.
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Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells
Cristina Zibetti, Sheng Liu, Jun Wan, Jiang Qian, Seth Blackshaw
bioRxiv 238279; doi: https://doi.org/10.1101/238279
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Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells
Cristina Zibetti, Sheng Liu, Jun Wan, Jiang Qian, Seth Blackshaw
bioRxiv 238279; doi: https://doi.org/10.1101/238279

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