Abstract
AbstractThe genome in the human cell is extraordinarily compacted in the nucleus. As a result, much of the DNA is inaccessible and functionally inert. Notwithstanding the highly efficient packaging, mechanisms have evolved to render DNA sites accessible that then enable a multitude of factors to carry out ongoing and vital functions. The compaction is derived from DNA complexation within nucleosomes, which can further consolidate into a higher-order chromatin structure. The nucleosome and nucleosomal DNA are not static in nature, but are dynamic, undergoing structural and functional changes as the cell responds to stresses and/or metabolic or environmental cues. We are only beginning to understand the forces and the complexes that engage the nucleosome to unearth the tightly bound and inaccessible DNA sequences and provide an opening to more accessible target sites. In many cases, current findings support a major role for the action of ATP-dependent chromatin remodeling complexes (CRCs) in providing an avenue to factor accessibility that leads to the activation of transcription. The estrogen receptor α (ERα) does not bind to the estrogen response element (ERE) in the canonical nucleosome. However, evidence will be presented that HMGB1 restructures the nucleosome in an ATP-independent manner and also facilitates access and strong binding of ERα to ERE. The features that appear important in the mechanism of action for HMGB1 will be highlighted, in addition to the characteristic features of the restructured nucleosome. These findings, together with previous evidence, suggest a collaborative role for HMGB1 in the step-wise transcription of estrogen-responsive genes. In addition, alternate mechanistic pathways will be discussed, with consideration that “HMGB1 restructuring” of the nucleosome may generally be viewed as a perturbation of the equilibrium of an ensemble of nearly isoenergetic nucleosome states in an energy landscape that is driven by conformational selection by HMGB1.
Highlights
One of the clear differences between histone H1 and HMGB1 is that H1 promotes and stabilizes higher-order chromatin or compaction, which limits access and inhibits transcription, while HMGB1 is found in more open chromatin structures, can increase accessibility and facilitates transcriptional initiation [116]
estrogen receptor (ER) is incapable of binding to the consensus ERE (cERE) in the canonical nucleosome
The binding affinity increased 10-fold, from a Kd ~300 nM in the canonical nucleosome to 30 nM in the restructured nucleosomes, which is only three times weaker than ER binding to naked DNA
Summary
The genetic material in a human cell—three billion base pairs (bps) of DNA—which when extended is 2 meters in length, is enormously compacted in the relatively microscopic cellular nucleus (10 microns (10 × 10−6 m) in diameter). The conventional model for transcriptional activation proposes that a regulatory or activator protein initiates the process by binding to its DNA response element embedded in the nucleosome or in a ―nucleosome-free‖ region This activator/DNA complex provides the initial ―target‖ to recruit a variety of factors that, as noted above, enzymatically modify the core histones by posttranslational modification which provide the specific platforms to further recruit ATP-dependent CRCs and coregulators. And in addition to the findings that HMGB1 binds in the pS2 promoter during the early stages of transcription [63], these collective findings provide evidence that HMGB1 plays a significant role in the regulation of this model estrogen-responsive system, in addition to estrogen-mediated gene expression at the pS2 promoter in MCF-7 cells These studies led directly into investigating whether the effect observed for HMGB1 on transcription could be directly linked to an alteration in the structure of the nucleosome and, if so, would this have an influence on ER/cERE binding. ER Substrate Canonical N N (w 400 nM HMGB1) Ntl Ntl (w 400 nM HMGB1) N‘/N‘‘ (1600 nM HMGB1 followed by sed. to 12 nM) DNA
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