Epigenetic basis of retinal cell fate determination

SUMMARY: Progressive loss of retinal ganglion cells (RGCs) and subsequent degeneration of
optic nerve is among the most common ophthalmic neuropathies that affect populations
worldwide. A promising therapeutic strategy relies on using stem cells to reconstruct functional
retinal ganglion cells in vitro that can be used to replace dying cells in affected patients. However,
for this strategy to be successful, a thorough understanding to the molecular mechanisms of RGC
specification and differentiation are needed to elucidate and exploit normal RGC developmental
pathways and thereby maximize RGC generation for cell replacement therapies. Our previous
work has mapped the epigenetic landscape dynamics during mouse and human developing
retina. However, there is a fundamental gap in our knowledge to the role of 3D chromatin topology
in RGC development and maintenance. Experiments in this proposal will address this role by
combining innovative state of the art genomic and genetic tools to elucidate the chromatin
architecture dynamics that accompany RGC genesis and to determine how they function in vivo.
Our central hypothesis is that temporal and spatial regulation of ganglion cell genesis is
associated with dynamic 3D genomic interactions between specific non-coding DNA elements
and genes that drive RGC differentiation and optic nerve growth. To test this hypothesis, we will
elucidate the link between 3D chromatin architecture and the expression of a transcription factor
essential for RGC formation. We will also dissect the functional significance of constituents of the
regulatory landscape that accommodates RGC differentiation in vivo. Finally, we will integrate
ChIP-Seq data with techniques that map chromatin topology to elucidate the long-range genomic
interactions that are associated with components of the regulatory networks that are required for
RGC differentiation. When completed the results of this proposal will advance our understanding
to the 3D regulatory landscape that accommodates the generation of RGCs in vivo, a necessary
knowledge to enhance RGC replacement therapies in RGC degenerative diseases.
Project Summary- Al Diri 1

Grant Number: 5R01EY030861-05
NIH Institute/Center: NIH
Principal Investigator: Issam Al Diri