Topological demarcation by HMGB2 is disrupted early upon senescence entry across cell types and induces CTCF clustering

Zirkel, Anne; Nikolić, Miloš; Sofiadis, Konstantinos; Mallm, Jan‐Philipp; Brant, Lilija; Becker, Christian; Altmueller, Janine; Franzen, Julia; Koker, Mirjam; Gusmao, Eduardo Gade; Costa, Ivan G.; Ullrich, Rolland T; Wagner, Wolfgang; Nüernberg, Peter; Rippe, Karsten; Papantonis, Argyris

doi:10.1101/127522

Cited by 8 publications

(5 citation statements)

References 80 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, we showed that both CTCF and cohesin form small protein clusters 7 and a recent study found that CTCF can form large foci upon senescence, which causes genome reorganization. 74 Thus, detailed studies on the nuclear organization of CTCF and cohesin should be informative. Fifth, absolute quantification of CTCF boundary permeability (i.e.…”

Section: Discussionmentioning

confidence: 99%

Recent evidence that TADs and chromatin loops are dynamic structures

Hansen

Cattoglio

Darzacq

et al. 2017

Nucleus

228

194

View full text Add to dashboard Cite

Mammalian genomes are folded into spatial domains, which regulate gene expression by modulating enhancer-promoter contacts. Here, we review recent studies on the structure and function of Topologically Associating Domains (TADs) and chromatin loops. We discuss how loop extrusion models can explain TAD formation and evidence that TADs are formed by the ring-shaped protein complex, cohesin, and that TAD boundaries are established by the DNA-binding protein, CTCF. We discuss our recent genomic, biochemical and single-molecule imaging studies on CTCF and cohesin, which suggest that TADs and chromatin loops are dynamic structures. We highlight complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model. We discuss the limitations of each approach and conclude that in aggregate the available evidence argues against stable loops and supports a model where TADs are dynamic structures that continually form and break throughout the cell cycle.

show abstract

Section: Discussionmentioning

confidence: 99%

Recent evidence that TADs and chromatin loops are dynamic structures

Hansen

Cattoglio

Darzacq

et al. 2017

Nucleus

228

194

View full text Add to dashboard Cite

show abstract

“…Considering a circular polymer as a substrate not only mimics bacterial plasmids and DNA mini-rings but also stably looped genomic regions in eukaryotes. These regions may be looped by chromatin-binding proteins such as transcription factors (e.g., HMGB2 [81]) and Polymerases, but also by CTCF [59] in the case of TADs.…”

Section: Circular Polymers Mimic Plasmids or Stably Looped Genomic Re...mentioning

confidence: 99%

Synergy of topoisomerase and structural-maintenance-of-chromosomes proteins creates a universal pathway to simplify genome topology

Orlandini

Marenduzzo

Michieletto

2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Topological entanglements severely interfere with important biological processes. For this reason, genomes must be kept unknotted and unlinked during most of a cell cycle. Type II topoisomerase (TopoII) enzymes play an important role in this process but the precise mechanisms yielding systematic disentanglement of DNA in vivo are not clear. Here we report computational evidence that structural-maintenance-of-chromosomes (SMC) proteins—such as cohesins and condensins—can cooperate with TopoII to establish a synergistic mechanism to resolve topological entanglements. SMC-driven loop extrusion (or diffusion) induces the spatial localization of essential crossings, in turn catalyzing the simplification of knots and links by TopoII enzymes even in crowded and confined conditions. The mechanism we uncover is universal in that it does not qualitatively depend on the specific substrate, whether DNA or chromatin, or on SMC processivity; we thus argue that this synergy may be at work across organisms and throughout the cell cycle.

show abstract

“…Yet, the genome is poorly represented by a 1D array of Ising spins. Instead, it is a fluctuating polymer which can assume distinct spatial organisations in 3D and also in response to stimuli [15,16] and epigenetic cues [3].…”

mentioning

confidence: 99%

Nonequilibrium Theory of Epigenomic Microphase Separation in the Cell Nucleus

et al. 2019

View full text Add to dashboard Cite

Understanding the spatial organisation of the genome in the cell nucleus is one of the current grand challenges in biophysics. Certain biochemical -or epigenetic -marks that are deposited along the genome are thought to play an important, yet poorly understood, role in determining genome organisation and cell identity. The physical principles underlying the interplay between epigenetic dynamics and genome folding remain elusive. Here we propose and study a theory that assumes a coupling between epigenetic mark and genome densities, and which can be applied at the scale of the whole nucleus. We show that equilibrium models are not compatible with experiments and a qualitative agreement is recovered by accounting for non-equilibrium processes which can stabilise microphase separated epigenomic domains. We finally discuss the potential biophysical origin of these terms.Establishing distinct and inheritable cellular identities in different tissues is crucial to the existence of complex multi-cellular organisms. Because all cells contain the same DNA, cellular fate cannot be directed by genetic cues alone. Instead, tissue-specific 3D genome organisation [1] and biochemical (also called epigenetic) patterns [2] are thought to be key regulators of cellular fate [3]. Epigenetic patterns are composed of biochemical marks on DNA and histones -the proteins which package DNA into chromatin [4] -and can be deposited or removed by a range of specialised proteins [2] often recruited by complexes such as RNA polymerase [5] and Polycomb Repressive Complex (PRC) [6].Investigating the interplay between genome organisation and epigenetic patterns can shed light into the mechanism underlying cell fate decision [7,8]. To study the dynamics of epigenetic patterns, Ising-like models have been proposed in the biophysics literature [9][10][11][12][13][14]. Yet, the genome is poorly represented by a 1D array of Ising spins. Instead, it is a fluctuating polymer which can assume distinct spatial organisations in 3D and also in response to stimuli [15,16] and epigenetic cues [3].In this Letter, and the companion paper [17], we aim to analyse the link between chromatin large-scale organisation and epigenetic dynamics by using models for chromatin folding inspired by the physics of magnetic polymers [18]. We study a Landau-Ginzburg field theory where the dynamics of epigenetic marks is linked to that of genome folding within the nucleus. Our theory considers a 1D chain of Potts-like spins which is allowed to fluctuate in 3D. It markedly departs from previous works [19,20] as we formalise and study a theory for the epigenomic organisation of a whole eukaryotic nucleus and investigate how non-equilibrium processes affect its thermodynamics and kinetics.We show that while an equilibrium theory for epigenomic organisation captures some features seen in vivo, such as segregation of different epigenetic marks, it fails to explain the experimentally observed coexistence of diverse epigenetic and genomic domains in eukaryotic nuclei [2,21]. In light of...

show abstract

Topological demarcation by HMGB2 is disrupted early upon senescence entry across cell types and induces CTCF clustering

Cited by 8 publications

References 80 publications

Recent evidence that TADs and chromatin loops are dynamic structures

Recent evidence that TADs and chromatin loops are dynamic structures

Synergy of topoisomerase and structural-maintenance-of-chromosomes proteins creates a universal pathway to simplify genome topology

Nonequilibrium Theory of Epigenomic Microphase Separation in the Cell Nucleus

Contact Info

Product

Resources

About