Chromatin plasticity: A versatile landscape that underlies cell fate and identity

Yadav, Tejas; Quivy, Jean‐Pierre; Almouzni, Geneviève

doi:10.1126/science.aat8950

Cited by 169 publications

(124 citation statements)

References 58 publications

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“…Our results suggest a global coupling between different chromatin properties including domain hierarchy, nanocluster size distribution, backbone openness, packing heterogeneity, genomic interaction, and transcriptional polarization, which means a significant dimensionality reduction during chromatin folding due to the emergence of collective folding parameters or susceptibilities (α in SRRW for example). Such folding picture sheds new lights into the physics of epigenetics [65][66][67] and chromatin plasticity 68 , and stresses the importance of understanding 3D genome from a data structure point of view (Fig. 1F) on top of polymer physics, since chromatin folding is optimizing biological functions rather than minimizing thermodynamic free energy.…”

Section: Discussionmentioning

confidence: 89%

Physical and data structure of 3D genome

Huang¹,

Shim³

et al. 2019

Preprint

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With the textbook view of chromatin folding based on the 30nm fiber being challenged, it has been proposed that interphase DNA has an irregular 10nm nucleosome polymer structure whose folding philosophy is unknown. Nevertheless, experimental advances suggested that such irregular packing is associated with many nontrivial physical properties that are puzzling from a polymer physics point of view. Here, we show that the reconciliation of these exotic properties necessitates modularizing 3D genome into tree data structures on top of, and in striking contrast to the linear topology of DNA double helix. Such functional modules need to be connected and isolated by an open backbone that results in porous and heterogeneous packing in a quasi-self-similar manner as revealed by our electron and optical imaging. Our multi-scale theoretical and experimental results suggest the existence of higher-order universal folding principles for a disordered chromatin fiber to avoid entanglement and fulfill its biological functions.

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Section: Discussionmentioning

confidence: 89%

Physical and data structure of 3D genome

Huang¹,

Shim³

et al. 2019

Preprint

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“…The dynamic maintenance of chromatin structure is required for maintaining both genome and epigenome stability and regulating cell fate (Alabert and Groth, 2012;Yadav et al, 2018). ATR/CHK1-mediated DDR signaling is linked to the maintenance of chromatin structure through the regulation of Tousled like kinase activity (TLK) (Groth et al, 2003;Krause et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling

Segura-Bayona

Villamor-Payà

Attolini

et al. 2019

Preprint

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The Tousled like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperones and are regulated by the DNA damage response. Depletion of TLK activity caused replication stress, increased chromosomal instability and cell arrest or death.Here, we show that stalled forks in TLK depleted cells are processed by BLM, SAMHD1 and the MRE11 nuclease to generate ssDNA and activate checkpoint signaling. TLK depletion also impaired heterochromatin maintenance, inducing features of alternative lengthening of telomeres and increasing spurious expression of other repetitive elements, associated with impaired deposition of the histone variant H3.3. TLK depletion culminated in a BLMdependent, STING-mediated innate immune response. In many human cancers, TLK1/2 expression correlated with signatures of chromosomal instability and anti-correlated with STING and innate and adaptive immune response signatures. Together, our results show that TLK activity protects replication forks from active processing, contributes to chromatin silencing and suppresses innate immune responses, suggesting that TLK amplification may protect chromosomally unstable cancers from immune detection.

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“…Eu- and hetero-chromatin domains are not absolute, but subject to alteration during development, neoplasia, and aging 35,57,58 . It will be of interest to determine the influence of these changes on the response to replication stress by DONSON and FANCM associated replisomes.…”

Section: Discussionmentioning

confidence: 99%

DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

Zhang

Bellani

James

et al. 2020

Preprint

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25Duplication of mammalian genomes requires replisomes to overcome numerous impediments 26 during passage through open (eu) and condensed (hetero) chromatin. Typically, studies of 27 replication stress characterize mixed populations of challenged and unchallenged replication forks, 28 averaged across S phase, and model a single species of "stressed" replisome. However, in cells 29 containing potent obstacles to replication, we find two different lesion proximal replisomes. One 30 is bound by the DONSON protein and is more frequent in early S phase, in regions marked by 31 euchromatin. The other interacts with the FANCM DNA translocase, is more prominent in late S 32 phase, and favors heterochromatin. The two forms can also be detected in unstressed cells. CHIP-33 seq of DNA associated with DONSON or FANCM confirms the bias of the former towards regions 34 that replicate early and the skew of the latter towards regions that replicate late. 35Introduction 36 Eukaryotic replisomes are multiprotein complexes consisting, minimally, of the CMG 37 helicase [MCM2-7 (M), CDC45 (C), and GINS (go, ichi, ni, san) proteins (G)] which forms a ring 38 around the leading strand template. Other components include the pol α, ε, and δ polymerases, 39 MCM10, and a few accessory factors [1][2][3][4][5][6][7] . The identification and characterization of the minimal 40 components of biochemically active replisomes, the result of decades of extraordinary work from 41 multiple laboratories, necessarily reflects studies with deproteinized model DNA substrates under 42 carefully controlled conditions. However, in vivo there are hundreds of replisome associated 43 proteins 8-12 . Presumably this reflects the multiple layers of complexity that characterize replication 44 of the genome in living cells. For example, three dimensional analyses of chromosome structure 45 demonstrate two major domains. The A compartment contains euchromatin, which is accessible, 46 transcriptionally active, and marked by specific histone modifications, such as H3K4me3. The B 47 compartment, which is more condensed, contains inactive genes, many repeated elements, and is 48 associated with different histone modifications, including H3K9me3 13 . In addition to the structural 49 distinctions, regions of the genome are also subject to temporal control of replication during S 50 phase. Sequences in Compartment A tend to replicate early in S phase, while those in B are 51 duplicated in late S phase 14,15 . 52 Other influential effectors of replisome composition are the frequent encounters with 53 impediments, that stall or block either the progress of the CMG helicase or DNA synthesis. These 54 3 include alternate DNA structures, protein: DNA adducts, DNA covalent modifications introduced 55 by endogenous or endogenous reactants, depleted nucleotide precursor pools, etc. Replication 56 stress activates the ATR (ATM-and Rad3-related) kinase, with hundreds of substrates, including 57 MCM proteins [16][17][18] , and stimulates the recruitment of numerous facto...

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Chromatin plasticity: A versatile landscape that underlies cell fate and identity

Cited by 169 publications

References 58 publications

Physical and data structure of 3D genome

Physical and data structure of 3D genome

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling

DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

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