DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Du, Qiyun; Smith, Grady C.; Luu, Phuc-Loi; Ferguson, James M.; Armstrong, Nicola J.; Caldon, C. Elizabeth; Campbell, E.; Nair, Shalima S.; Zotenko, Elena; Gould, Cathryn M.; Buckley, Michael; Kaczorowski, Dominik C.; Barton, Kirston; Smith, Martin A.; Powell, Joseph E.; Skvortsova, Ksenia; Stirzaker, Clare; Achinger-Kawecka, Joanna; Clark, Susan J.

doi:10.1101/2020.10.15.338855

Cited by 3 publications

(3 citation statements)

References 109 publications

(152 reference statements)

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“…3i). In agreement with prior studies, DNMT1 inhibition reduced genome compartmentalization on a global scale 34,50,51 , which is reflected by the decreased ratio of intra-to inter-compartment interactions as well as broad compartment shifts, with B regions becoming more A-like and vice versa (Fig. 3a).…”

Section: Resultssupporting

confidence: 92%

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

et al. 2022

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The genome can be divided into two spatially segregated compartments, A and B, which partition active and inactive chromatin states. While constitutive heterochromatin is predominantly located within the B compartment near the nuclear lamina, facultative heterochromatin marked by H3K27me3 spans both compartments. How epigenetic modifications, compartmentalization, and lamina association collectively maintain heterochromatin architecture remains unclear. Here we develop Lamina-Inducible Methylation and Hi-C (LIMe-Hi-C) to jointly measure chromosome conformation, DNA methylation, and lamina positioning. Through LIMe-Hi-C, we identify topologically distinct sub-compartments with high levels of H3K27me3 and differing degrees of lamina association. Inhibition of Polycomb repressive complex 2 (PRC2) reveals that H3K27me3 is essential for sub-compartment segregation. Unexpectedly, PRC2 inhibition promotes lamina association and constitutive heterochromatin spreading into H3K27me3-marked B sub-compartment regions. Consistent with this repositioning, genes originally marked with H3K27me3 in the B compartment, but not the A compartment, remain largely repressed, suggesting that constitutive heterochromatin spreading can compensate for H3K27me3 loss at a transcriptional level. These findings demonstrate that Polycomb sub-compartments and their antagonism with lamina association are fundamental features of genome structure. More broadly, by jointly measuring nuclear position and Hi-C contacts, our study demonstrates how compartmentalization and lamina association represent distinct but interdependent modes of heterochromatin regulation.

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Section: Resultssupporting

confidence: 92%

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

et al. 2022

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“…At a global level, EZH2 and DNMT1 inhibition led to largely contrasting changes in compartmentalization with DNMT1 inhibition impacting compartmentalization to a larger degree than EZH2 inhibition ( Fig 3a-c, Fig S3i ). In agreement with prior studies, DNMT1 inhibition reduced genome compartmentalization on a global scale, 35,50,51 which is reflected by the decreased ratio of intra-to inter-compartment interactions as well as broad compartment shifts, with B regions becoming more ‘A-like’ and vice versa ( Fig 3a ). At the sub-compartment level, these shifts included strengthened interactions between Core-B and both A sub-compartments ( Fig 3b, Fig 3d ).…”

Section: Resultssupporting

confidence: 92%

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

Siegenfeld

Roseman

Roh

et al. 2022

Preprint

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The genome can be divided into two spatially segregated compartments, A and B,1,2 which broadly partition active and inactive chromatin states, respectively. Constitutive heterochromatin is predominantly located within the B compartment and comprises chromatin that is in close contact with the nuclear lamina.3–5 By contrast, facultative heterochromatin marked by H3K27me3 can span both compartments.2–5 How epigenetic modifications, A/B compartmentalization, and lamina association collectively maintain heterochromatin architecture and function remains unclear.6,7 Here we developed an approach termed Lamina-Inducible Methylation and Hi-C (LIMe-Hi-C) that jointly measures chromosome conformation, DNA methylation, and nuclear lamina positioning. Through this approach, we identified topologically distinct A/B sub-compartments characterized by high levels of H3K27me3 and differing degrees of lamina association. To study the regulation of these sub-compartments, we inhibited Polycomb repressive complex 2 (PRC2), revealing that H3K27me3 is an essential factor in sub-compartment segregation. Unexpectedly, PRC2 inhibition also elicited broad gains in lamina association and constitutive heterochromatin spreading into H3K27me3-marked B sub-compartment regions. Consistent with repositioning to the lamina, genes originally marked with H3K27me3 in the B compartment, but not in the A compartment, remained largely repressed, suggesting that constitutive heterochromatin spreading can compensate for loss of H3K27me3 at a transcriptional level. These findings demonstrate that Polycomb sub-compartments and their antagonism with nuclear lamina association are fundamental organizational features of genome structure. More broadly, by jointly measuring nuclear position and Hi-C contacts, our study demonstrates how dynamic changes in compartmentalization and nuclear lamina association represent distinct but interdependent modes of heterochromatin regulation.

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“…DNA hypermethylation at CTCF binding site in IDH mutant gliomas results in its reduced CTCF binding, loss of insulation between topological domains and aberrant gene activation 16 . More recently, DNA hypomethylation has been shown to result in de-compaction of chromatin and loss of compartmental organisation 53,56,62,63 . This is consistent with our data showing closed (B-type) to active (A-type) compartment shifting with Decitabine-induced DNA hypomethylation and reduced interactions between B-type compartments.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

Achinger-Kawecka

Stirzaker

Chia

et al. 2021

Preprint

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Three-dimensional (3D) epigenome remodelling is emerging as an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome cancer therapy resistance remains largely unaddressed. Here we show that treatment of endocrine-resistant estrogen receptor positive (ER+) breast cancer with an FDA-approved epigenetic therapy Decitabine (5-Aza-mC), results in genome-wide DNA hypomethylation and suppression of tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Systematic integration of matched chromatin conformation capture (Hi-C), Promoter Capture Hi-C, RNA-seq and ER ChIP-seq data revealed widespread effects on epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associating domains (TAD) boundary insulation. Key enhancer ER binding sites were demethylated and re-activated after Decitabine treatment, resulting in new ER mediated enhancer-promoter interactions and concordant activation of tumour suppressive gene pathways. Importantly, we show that the activated ER target genes were also predictive of good outcome in multiple ER+ breast cancer clinical cohorts. Together our study reveals a previously undescribed mechanism of Decitabine in re-wiring DNA methylation-dependent 3D genome architecture resulting in suppression of tumour growth, and highlights the potential of epigenetic therapy in targeting ER+ endocrine-resistant breast cancer.

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DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Cited by 3 publications

References 109 publications

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

Polycomb-lamina antagonism partitions heterochromatin at the nuclear periphery

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

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