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Publications of the Week

Single-Cell ATAC-Seq of Fetal Human Retina and Stem-Cell-Derived Retinal Organoids Shows Changing Chromatin Landscapes during Cell Fate Acquisition

By February 7, 2022No Comments

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This week we profile a recent publication in Cell Reports from the laboratory of Dr. Thomas Reh at the Institute for Stem Cells and Regenerative Medicine at UW.

Can you provide a brief overview of your lab’s current research focus?

Our lab studies the development and regeneration of the retina, with the hope of ultimately applying this approach to restoring sight to people that are blind from the loss of retinal cells. Through an understanding of how retinal neurons arise from progenitors in fetal development, we have been able to devise ways to reinitiate the developmental process in mature mouse retinas, to restore functional neurons.  We are working to find additional developmental factors to better enable our regeneration strategies.
What is the significance of the findings in this publication?
The mechanisms that enable progenitor cells to generate a wide variety of neurons during development are still a mystery.  We know that many transcription factors are involved in this process, but up to now, we have not been able to put them together to understand how they control these diverse fates.  In this study, we used a relatively new technique, single-cell ATACseq, to reveal the transcriptional networks that control fate decisions and the sequence or cascade of activity of these factors.  We did this work in fetal human retina, to establish a reference atlas of developing retinal “accessible chromatin” giving insight into cell-type-specific cis-regulatory mechanisms, and we further used the data from normal fetal development to benchmark the cells from retinal organoids derived from iPSCs.  By comparing normal fetal development with iPSC-derived retinal organoids, we were able to detect differences between the two that we hope will allow the generation of better iPSC-derived retinal models for eye disease.
What are the next steps for this research?
The published work provides a roadmap for both improving retinal disease models and for candidate transcription factors to aid in our efforts to stimulate endogenous retinal repair.  We have found in the past few years that a single transcription factor, Ascl1, can stimulate retinal regeneration from glial cells, called Muller glia.  However, the regeneration we see from using Ascl1 is only partial, and many of the key retinal cells types are not regenerated.  This new study has revealed dozens of additional transcription factor candidates that we will now use in assays of retinal regeneration to stimulate more complete retinal repair.
If you’d like us to mention your funding sources, please list them.
We are grateful to the Foundation Fighting Blindness and the Paul Allen Family Foundation for support of this work at an early stage when TAR was an Allen Distinguished Investigator

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