RASSF1 is identified by transcriptome coordination analysis as a target of ATF4

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Gene co-regulation analysis is crucial for understanding gene function and regulatory networks.
• The unfolded protein response (UPR) is a critical cellular pathway involved in endoplasmic reticulum (ER) stress.
• Identifying novel regulators of UPR is essential for understanding cellular responses to stress.

Purpose of the Study:

• To investigate gene co-regulation patterns in deer mice fibroblasts.
• To identify transcripts co-regulated with UPR genes.
• To explore the functional role of RASSF1 in UPR-associated processes.

Main Methods:

• Transcriptome analysis of cultured deer mouse fibroblasts.
• Bioinformatic analysis of gene co-expression networks.
• Chromatin immunoprecipitation (ChIP) assays.
• Reporter assays to assess promoter activity.
• Gene knockout studies to evaluate RASSF1 function.

Main Results:

• RASSF1 transcripts were highly correlated with several UPR-related genes, including BiP/GRP78, DNAJB9, GRP94, ATF4, DNAJC3, and CHOP/DDIT3.
• Genes co-regulated with RASSF1 were predicted to be involved in UPR-associated apoptosis.
• ATF4-binding sites were identified in the RASSF1 promoter and shown to be functional.
• RASSF1 ablation affected ATF4 effector BBC3 expression and abrogated tunicamycin-induced apoptosis.

Conclusions:

• RASSF1 plays a role in regulating ER stress-associated apoptosis downstream of ATF4.
• Gene co-regulation analysis is a powerful tool for predicting biological functions and uncovering gene regulatory relationships.
• This study reveals a novel link between RASSF1 and the UPR pathway.