July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Author Affiliations & Notes
  • Ales Cvekl
    Ophthalmology & Vis Sci & Genetics, Albert Einstein Coll of Medicine, Bronx, New York, United States
  • Yilin Zhao
    Ophthalmology & Vis Sci & Genetics, Albert Einstein Coll of Medicine, Bronx, New York, United States
  • Deyou Zheng
    Ophthalmology & Vis Sci & Genetics, Albert Einstein Coll of Medicine, Bronx, New York, United States
  • Footnotes
    Commercial Relationships   Ales Cvekl, None; Yilin Zhao, None; Deyou Zheng, None
  • Footnotes
    Support  NIH Grant R01EY012200 and EY014237
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3300. doi:
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    • Get Citation

      Ales Cvekl, Yilin Zhao, Deyou Zheng; CHROMATIN DYNAMICS, PROMOTERS, ENHANCERS, AND LENS DIFFERENTIATION. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3300.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Promoters and enhancers are cis-regulatory DNA sequences that control transcription. Both these sequences are comprised of clusters of cis-sites that interact with sequence-specific DNA binding transcription factors, including signal regulated transcription factors. When active, these regions are detectable as “open” chromatin, display increased nuclease sensitivity, contain nucleosome-free regions, and their nucleosomes are marked by specific combinations of modified core histones. Together, “open” and “closed” chromatin domains represent transcriptionally poised or active and repressed states of individual genes, respectively. Dynamic changes in local chromatin structure of numerous genes occur during cellular differentiation.

Methods : To study chromatin structure and dynamics, ATAC-seq experiments were conducted using mouse epithelia and fibers from E14.5 and P1 lenses. RNA-seq data on lens transcriptome, Pax6 binding, and histone modification profiles were also incorporated into the analysis.

Results : We identified dynamics of open chromatin changes by defining differentially accessible regions during mouse lens fiber cell (Path1: epiE14.5"fibE14.5"fibP1) and epithelium (Path2: epiE14.5"epiP1) differentiation. The data were coupled with differential gene expression, yielding 6 and 3 mRNA clusters, in Path1 and 2, respectively. Unbiased cis-motif analysis of “open” regions, corresponding to promoters and enhancers, revealed the cis-regulatory logic of lens differentiation via known (e.g. AP-1, Etv, Maf, and Pax6) and novel (e.g. CTCF, Tead, and NRF1) motifs. Pax6 was bound both in “open” and “closed” lens chromatin domains in agreement with its dual roles as transcriptional activator and repressor. Lens-specific regulatory regions are shown using ES cells, forebrain, and liver.

Conclusions : Our studies support a general model of stage-specific changes in open chromatin associated with transcriptional activities of batteries of genes required for lens fiber cell formation. Analysis of promoters and enhancers reveals enrichment of cis-motifs that establish the molecular foundation for temporally and spatially regulated gene expression in lens. Together, the data open the field for mechanistic studies of lens-specific enhancers, reconstruction of GRNs that govern lens morphogenesis, and identification of cataract-causing mutation in non-coding sequences.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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