September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
ChIPseq profiling of histone modification changes reveals gene misregulation mechanisms in mouse models of photoreceptor disease.
Author Affiliations & Notes
  • Philip Andrew Ruzycki
    Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
    Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
  • Xiaodong Zhang
    Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
  • Shiming Chen
    Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
    Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
  • Footnotes
    Commercial Relationships   Philip Ruzycki, None; Xiaodong Zhang, None; Shiming Chen, None
  • Footnotes
    Support  NIH R01EY012543 (to SC), EY025272 (to SC), P30EY002687 and T32EY013360 (to WU-DOVS)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4816. doi:
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      Philip Andrew Ruzycki, Xiaodong Zhang, Shiming Chen; ChIPseq profiling of histone modification changes reveals gene misregulation mechanisms in mouse models of photoreceptor disease.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4816.

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

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Abstract

Purpose : Mutations in the transcription factors CRX and NRL disrupt normal photoreceptor development and survival. Previous genome-wide assays provided insight into CRX/NRL target genes and regulatory roles, but did not address chromatin structure modulation. This study was designed to close this gap. We focused on developmental changes of gene activation-associated histone modifications in wild-type and Crx or Nrl deficient mice.

Methods : Chromatin immunoprecipitation-sequencing (ChIPseq) assays were used to profile the genome-wide occupancy of two activation-associated histone H3 modifications: tri-methylation of Lysine 4 (H3K4me3) and acetylation of Lysine 27 (H3K27Ac), in the retinas of wild-type and Crx- or Nrl-deficient mice before and after photoreceptor differentiation. The results were analyzed alongside published RNAseq, ChIPseq and DnaseI hypersensitivity datasets to identify pathogenic epigenetic alterations that correlate with transcription misregulation.

Results : The H3K4me3 and H3K27Ac marks on ChIPseq-identified CRX/NRL target genes in WT retinas significantly increased during postnatal photoreceptor differentiation, which was closely associated with gene activation. These dynamic changes of active histone marks were altered in Crx or Nrl deficient retinas. The prevalence and degree of the alterations correlated with gene expression changes and phenotype severity. Thus, dynamic epigenetic regulation is essential for appropriate expression of the genes necessary for photoreceptor cell fate and function, and CRX and/or NRL function is required for this to occur.

Conclusions : CRX and NRL both act as positive chromatin modulators, as their presence is required for activation-associated epigenetic changes on target genes. Genome-wide profiling of epigenetic changes provides a deeper understanding of the mechanisms by which transcription factor mutations cause misregulation of gene expression and disease phenotype.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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