Nucleosome Distortion as a Possible Mechanism of Transcription Activation Domain Function

After more than three decades since the discovery of transcription activation domains (ADs) in gene-specific activators, the mechanism of their function remains enigmatic. The widely accepted model of direct recruitment by ADs of co-activators and basal transcriptional machinery components, however, is not always compatible with the short size yet very high degree of sequence randomness and intrinsic structural disorder of natural and synthetic ADs. In this review, we formulate the basis for an alternative and complementary model, whereby sequence randomness and intrinsic structural disorder of ADs are necessary for transient distorting interactions with promoter nucleosomes, triggering promoter nucleosome translocation and subsequently gene activation

Activation of gene expression by detergent-like protein domains

The mechanisms by which transcriptional activation domains (tADs) initiate eukaryotic gene expression have been an enigma for decades because most tADs lack specificity in sequence, structure, and interactions with targets. Machine learning analysis of data sets of tAD sequences generated in vivo elucidated several functionality rules: the functional tAD sequences should (i) be devoid of or depleted with basic amino acid residues, (ii) be enriched with aromatic and acidic residues, (iii) be with aromatic residues localized mostly near the terminus of the sequence, and acidic residues localized more internally within a span of 20–30 amino acids, (iv) be with both aromatic and acidic residues preferably spread out in the sequence and not clustered, and (v) not be separated by occasional basic residues. These and other more subtle rules are not absolute, reflecting absence of a tAD consensus sequence, enormous variability, and consistent with surfactant-like tAD biochemical properties. The findings are compatible with the paradigm-shifting nucleosome detergent mechanism of gene expression activation, contributing to the development of the liquid-liquid phase separation model and the biochemistry of near-stochastic functional allosteric interactions

Different Requirements of the SWI/SNF Complex for Robust Nucleosome Displacement at Promoters of Heat Shock Factor and Msn2- and Msn4-Regulated Heat Shock Genes▿

The stress response in yeast cells is regulated by at least two classes of transcription activators—HSF and Msn2/4, which differentially affect promoter chromatin remodeling. We demonstrate that the deletion of SNF2, an ATPase activity-containing subunit of the chromatin remodeling SWI/SNF complex, eliminates histone displacement, RNA polymerase II recruitment, and heat shock factor (HSF) binding at the HSP12 promoter while delaying these processes at the HSP82 and SSA4 promoters. Out of the three promoters, the double deletion of MSN2 and MSN4 eliminates both chromatin remodeling and HSF binding only at the HSP12 promoter, suggesting that Msn2/4 activators are primary determinants of chromatin disassembly at the HSP12 promoter. Unexpectedly, during heat shock the level of Msn2/4 at the HSP12 promoter declines. This is likely a result of promoter-targeted Msn2/4 degradation associated with transcription complex assembly. While histone displacement kinetic profiles bear clear promoter specificity, the kinetic profiles of recovery from heat shock for all analyzed genes display an equal or even higher nucleosome return rate, which is to some extent delayed by the deletion of SNF2