HMGs as rheostats of chromosomal structure and cell proliferation

High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones. Changes in nuclear HMG levels drive changes in spatial genome organization. Nuclear depletion of HMG-box proteins (HMGBs) is a hallmark of senescence entry. Tumors are ‘addicted’ to HMG overexpression for aberrant proliferation. Changing HMGB levels correlates with changes in cell proliferation potency. High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones and are robustly expressed across tissues and organs. HMGs can uniquely bend or bind distorted DNA, and are central to such processes as transcription, recombination, and DNA repair. However, their dynamic association with chromatin renders capturing HMGs on chromosomes challenging. Recent work has changed this and now implicates these factors in spatial genome organization. Here, I revisit older and review recent literature to describe how HMGs rewire spatial chromatin interactions to sustain homeostasis or promote cellular aging. I propose a ‘rheostat’ model to explain how HMG-box proteins (HMGBs), and to some extent HMG A proteins (HMGAs), may control cellular aging and, likely, cancer progression. High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones and are robustly expressed across tissues and organs. HMGs can uniquely bend or bind distorted DNA, and are central to such processes as transcription, recombination, and DNA repair. However, their dynamic association with chromatin renders capturing HMGs on chromosomes challenging. Recent work has changed this and now implicates these factors in spatial genome organization. Here, I revisit older and review recent literature to describe how HMGs rewire spatial chromatin interactions to sustain homeostasis or promote cellular aging. I propose a ‘rheostat’ model to explain how HMG-box proteins (HMGBs), and to some extent HMG A proteins (HMGAs), may control cellular aging and, likely, cancer progression. chromatin immunoprecipitation coupled to massively parallel sequencing allowing mapping of transcription factor and histone mark positions along chromosomes. responsible for CpG methylation maintenance in mammalian cells with a preference for modifying hemimethylated DNA. characterized by the loss of epithelial-like features (like cell polarity and cell–cell adhesion) from cells gaining mesenchymal-like migratory and invasive properties; it is typically activated in cancer onset and metastasis. cells capable of differentiating into all three germ layers, endo-, meso-, and exoderm. an imaging method allowing the determination of diffusion kinetics of fluorescently tagged molecules inside cells. chromosome conformation capture assay allowing genome-wide interrogation of 3D chromatin folding. high mobility group A (formerly HMG-I(Y)/-I(C)) proteins. high mobility group-box (formerly HMG-1/-2) proteins. high mobility group N (formerly HMG-14/-17) proteins. cells capable of both chondrogenic and osteogenic differentiation. catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to generate nicotinamide mononucleotide during NAD+ metabolism. refers collectively to DNA structures that deviate from canonical right-handed B-form helix, like left-handed Z-DNA helices, hairpin, triplex, and cruciform structures or G4-quadruplexes. cells capable of generating neurons and glia. global transcriptome analysis via massively parallel sequencing of cellular RNA. formed by the spatial co-association of non-overlapping segments of facultative (H3K27me3-decorated) and constitutive (H3K9me3-decorated) heterochromatin. a cell type-specific mixture of molecules produced and secreted by senescent cells that confers proinflammatory potential and can drive paracrine senescence in a cell population. formed specifically upon entry into replicative senescence; they are triggered by the nuclear loss of HMGB2. systematic evolution of ligands by exponential enrichment allows discovery of the DNA sequences that transcription factors preferentially bind in vitro. Mbp-sized domains characterized by increased intra- compared to interdomain 3D chromatin interactions.