HDAC1/2 mediates the chloroplast unfolded protein response through histone H4 deacetylation in Chlamydomonas

Disruption of chloroplast proteostasis activates retrograde signaling that reprograms nuclear gene expression. However, how these signals are integrated with chromatin-based transcriptional regulation remains poorly understood. Here, using a genetic suppressor screen of a conditional ClpP1-depletion mutant, we identified a histone deacetylase HDAC1/2 as a regulator of chloroplast stress signaling in Chlamydomonas reinhardtii. Loss of HDAC1/2 alleviated growth inhibition and reduced cell death caused by disruption of chloroplast proteostasis following ClpP1 depletion. Furthermore, HDAC1/2 deficiency enhanced tolerance to high-light, oxidative, and endoplasmic reticulum stresses, as well as chloroplast translation inhibition. These stress conditions increased H₂O₂ levels and HDAC1/2 protein accumulation, suggesting that H₂O₂ may act as a common upstream signal. Additionally, HDAC1/2 deficiency also disrupted the transcriptional response to ClpP1 depletion, particularly affecting genes involved in photosynthesis, redox homeostasis, DNA metabolism, cell-cycle regulation, and ROS scavenging. This altered response was accompanied by increased histone H4 acetylation. Together, our findings identify HDAC1/2 as an important regulator connecting organellar proteostasis signaling with nuclear epigenetic regulation and suggest a role for H₂O₂ associated chromatin remodeling in coordinating cellular stress responses.