Fig. 8.

Rapid and coordinated reprogramming of genes and distal regulatory elements in stressed human cells. Model showing the rapid heat-induced response of the human genome, including reprogramming of gene transcription and establishment of a stress-specific repertoire of distal regulatory elements. Inhibition of the pause-release of promoter–proximal Pol II clears transcription complexes from the downregulated genes, elevating the concentration of free Pol II in the cell. The heat-induced genes are primed for directionality and rapid activation by the pre-assembled PIC on the core promoter of the coding strand, and by the paused Pol II at the 5′ region of the gene. Upon stress, trans-activators, such as HSF1, launch Pol II from the primed genes into productive elongation. The elevated levels of free Pol II and the highly positioned PIC on the coding strand enable instant loading of Pol II to the freed pause sites, efficiently launching rounds of transcript synthesis from the activated genes. The free Pol II allows also tuning up of the enhancer repertoire, increasing eRNA-production at dTREs that are marked by lineage-specific transcription factors, for example GATA1, GATA2 and TAL1 as shown in this study. In addition to reprogramming TREs, heat stress causes emergence of putative untranscribed regulatory elements, as demonstrated by the acetylation of histone H4 and recruitment of HSF1 to CTCF-rich loci that do not contain components of Pol II complex. Only the key regulatory factors discussed in the text are shown. ac, acetylation; CTCF, CCCTC-binding factor; Down, downregulated genes upon acute heat stress, dTRE, distal transcription regulatory element; dURE, distal untranscribed regulatory element; eRNA, enhancer RNA; GATA, GATA-binding protein; HSF1, heat shock factor 1; PIC, pre-initiation complex; P-TEFb, positive transcription elongation factor b; TAL1, T-cell acute lymphoid leukemia 1; TF, transcription factor, Up, upregulated genes or dTREs upon acute heat stress