Transcriptional response to stress is pre-wired by promoter and enhancer architecture

Abstract

Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profiled histone H4 acetylation in human cells. Our results globally show that the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene’s response to stress is determined. Highly transcribed and highly inducible genes display strong transcriptional directionality and selective assembly of general transcription factors on the core sense promoter. Heat-induced transcription at enhancers, instead, correlates with prior binding of cell-type, sequence-specific transcription factors. Activated Heat Shock Factor 1 (HSF1) binds to transcription-primed promoters and enhancers, and CTCF-occupied, non-transcribed chromatin. These results reveal chromatin architectural features that orient transcription at divergent regulatory elements and prime transcriptional responses genome-wide.

Molecular mechanisms driving transcriptional stress responses

“…These advances were harnessed to map the transcriptional changes upon heat stress at nucleotide resolution in multiple species. Analyses of the positions of transcribing Pol II complexes in fly 9 , mouse 10 and human 11 revealed the rapid repression of thousands of genes, as evidenced by the reduction of Pol II molecules along coding sequences (schematically illustrated in FIG. 2A).…”

“…2A). While the response in different species is highly conserved, in mammals, Pol II accumulates at the promoter-proximal pause region of heat-repressed genes 10,11 , whereas in flies, heat stress causes decreased Pol II density across the whole gene 9 . From fly to human, the rapid activation of hundreds of genes is detected as increased Pol II density both at promoter-proximal regions and along the coding sequences (FIG.…”

“…1). Throughout the decades, the profound molecular and physiological changes in stressed cells have provided robust models for elucidating mechanisms of key cellular processes, including the genome-wide coordination of transcription upon heat stress 9–11 (reviewed in 6,8,12 ), the molecular basis for inhibition of translation during Unfolded Protein Response (UPR) 13–14 (reviewed in 3,15 ), and the organismal control over cellular stress responses 16–17 (reviewed in 7,8 ). Additionally, properly regulated stress responses are vital for organismal health, as protein mis-folding and aggregation underlies neurodegeneration, while cancer cells can harness stress responses for improved cell survival and metastasis 18–22 (reviewed in 6,8,23 ).…”

“…However, recent advances in genome-wide methods have transformed conventional gene-centric analyses to characterization of regulatory mechanisms across the genome. Consequently, measures of the exact location of transcribing Pol II complexes across the genome have revealed the breath of gene and enhancer regulation upon heat and celastrol stresses, as well as the mechanistic steps at which the transcriptional reprogramming is executed 9–11,27–28 . Moreover, high-resolution chromatin analyses have uncovered stress-induced changes in nucleosome dynamics 29 , trans -activator binding 10,21,30–32 , and chromatin states 11,27,29 , both at transcribed and untranscribed loci.…”

Meeting Report – proteostasis in Ericeira

“…Danny Nedialkova (MPI of Biochemistry, Martinsried, Germany) followed up on the theme of codon-specific ribosome pausing, which causes the aggregation of many essential proteins and impairs the ability of cells to re-establish proteostasis (Nedialkova and Leidel, 2015). Lea Sistonen (Abo Akademi University, Turku, Finland) talked about the transcriptional regulation of proteostasis mediated by heat shock factor 1 (HSF1) (Vihervaara et al, 2017) and the epigenetic regulatory mechanisms that establish the transcriptional memory of stress. Claudina Rodrigues-Pousada (ITQB-NOVA, Oeiras, Portugal) followed up on the transcriptional regulation theme.…”