Nucleosome dynamics: HMGB1 facilitates nucleosome restructuring and collaborates in estrogen-responsive gene expression

Abstract

The 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.

 

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Keywords

nucleosome dynamics - HMGB1 - estrogen receptor α - conformational selection - energy landscape

Abbreviations

ER: estrogen receptor

ERE: estrogen response element

cERE: consensus estrogen response element

RE: response element

CRC: chromatin remodeling complex

HMGB1: high mobility group protein 1

HAT: histone acetyltransferase

HDAC: histone deacetylase

H3K9: histone H3, with modification at lysine 9

FoxA1: Forkhead-box protein A1

BRG-1 & hBrm: ATPase subunits in human CRCs

BAF: BRG1-asscoiated factor

PIC: preinitiation complex

TF: transcription factor

HSF: heat shock factor

NF1: nuclear factor1

TBP: TATA-binding protein

Max: myc-associated factor X

MMTV: mouse mammary tumor virus

TRF1: TTAGGG repeat binding factor-1

LEF-1: lymphoid enhancer binding factor-1

PR: progesterone receptor

GR: glucocorticoid receptor

TSS: transcription start site

MCF-7: Michigan Cancer Foundation cell line 7

TNF-α: tumor necrosis factor alpha

ISWI: imitation SWI

Kd: dissociation constant

KD: knock down

USF: up-stream stimulating factor

Sp1: specificity protein1

NF-κB1: nuclear factor kappa-light chain enhancer of activated B cells

Transcriptional coactivators: CBP, p300, pCAF, PBP, p160

ACF/CHRAC: ATP-utilizing chromatin remodeling factor/chromatin remodeling and assembly comple

 

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No conflict of interest has been declared by the author(s).

Publication History

Received: 08 October 2016

Accepted: 23 November 2016

Article published online:
10 May 2021