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Updated: Sep 11, 2025
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Multiplexed Analysis of Retinal Gene Expression and Chromatin Accessibility Using scRNA-Seq and scATAC-Seq
Published on: March 12, 2021
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Transcriptomic Profiling of Small Molecule Atf6 Modulators in the Retina
Monica Sophia Diaz-Aguilar1,2,3,4, Angela Galdamez1,2,3, Leon Chea1,2,3
1Department of Ophthalmology, Stanford University, Stanford, California, USA.
Summary
Small molecules targeting Activating Transcription Factor 6 (ATF6) show promise for retinal health. Researchers used RNA sequencing to confirm ATF6 inhibition and activation in mouse retinas without causing harm, paving the way for vision loss disease research.
Area of Science:
- Ophthalmology
- Molecular Biology
- Neuroscience
Background:
- The Unfolded Protein Response (UPR) is crucial for maintaining endoplasmic reticulum (ER) homeostasis and retinal health.
- Activating Transcription Factor 6 (ATF6) is a key regulator of the UPR, controlling genes that alleviate ER stress.
- Small molecule modulators of ATF6 have been developed but their in vivo effects, particularly in the retina, are not well understood due to detection limitations.
Purpose of the Study:
- To assess the in vivo effects of ATF6 small molecule modulators (Ceapin-A7 inhibitor, AA147 activator) in the mouse retina.
- To establish a sensitive method for detecting and quantifying ATF6 modulation in vivo.
- To determine the safety and potential of these modulators for future studies in vision loss disease models.
Main Methods:
- Targeted RNA sequencing (RNA-seq) was employed to analyze the transcriptional response in mouse retinas after intraocular delivery of Ceapin-A7 and AA147.
- Histological analysis and functional vision tests were performed to evaluate potential toxicity and visual impairment.
- Transcriptional analysis was used to confirm ER stress levels.
Main Results:
- Ceapin-A7 effectively suppressed ATF6 transcriptional targets, while AA147 induced ATF6-regulated genes in retinal tissue.
- Neither Ceapin-A7 nor AA147 treatment resulted in retinal cell death, vision compromise, or ER stress.
- The study successfully demonstrated a transcriptional strategy to sensitively monitor ATF6 modulation in vivo.
Conclusions:
- A novel RNA-seq based strategy enables sensitive detection of ATF6 small molecule modulator activity in vivo.
- Ceapin-A7 and AA147 can modulate ATF6 activity in the mouse retina without causing apparent toxicity or vision loss.
- These findings support the non-toxic use of these ATF6 modulators for further investigation in preclinical models of vision loss associated with ER stress.
