Heat shock or other proteotoxic stresses that cause the accumulation of misfolded proteins promote the conjugation of small ubiquitin-like modifier 2 (SUMO2) to nuclear proteins; the chromatin-binding profile of SUMO2 during heat shock is not fully characterized. By combining data from CHIP–seq and RNA-seq with previously published proteomics data, Hay and colleagues now find that, following heat shock, SUMO2 is conjugated to large protein complexes; these complexes are associated with the regulatory elements of active genes that encode regulators of gene expression and the post-transcriptional modification of RNA. SUMO2 did not directly activate or inhibit transcription, but its conjugation was required to maintain the maximal expression of target genes. The authors propose that sumoylation is an integral component of the proteotoxic stress response that helps to maintain the integrity of transcription regulatory protein complexes.