ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.

Endoplasmic reticulum (ER) stress triggers transcriptional programs that promote either adaptation or apoptosis, yet the epigenetic mechanisms underlying this response remain incompletely understood. Here, integrated multi-omics analyses of unfolded protein response transcription factor knockout cells identify ATF4 as a dominant regulator of ER stress-responsive enhancer activation and chromatin looping. Loss of ATF4 markedly impairs stress-induced H3K27ac accumulation and enhancer-promoter interactions at ATF4-associated regulatory elements, establishing ATF4 as a central organizer of the stress-responsive regulatory landscape. We further identify CHOP as a key functional partner of ATF4 during ER stress. Integrative analyses of ATF4 occupancy and H3K27ac landscapes in CHOP-knockout cells reveal that CHOP selectively modulates ATF4-dependent enhancer activity and controls distinct subsets of stress-responsive genes. This cooperation preferentially promotes apoptosis-associated transcriptional programs while having limited effects on core adaptive responses. Together, our findings define a hierarchical regulatory framework in which ATF4 establishes enhancer activation and chromatin looping networks, whereas CHOP selectively diversifies their output to specify ER stress-responsive gene programs.