3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome

Haws, Spencer A.; Simándi, Zoltán; Barnett, Robert; Phillips-Cremins, Jennifer E.

doi:10.1016/j.cell.2022.06.052

Cited by 24 publications

(13 citation statements)

References 172 publications

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“…Thus, similarly to the cis-regulatory elements of genes known as promoters and enhancers, RepSeq harbor cis-regulatory elements, which bind both activators and repressors, locally anchoring transcriptional activating and repressing systems, respectively (56–64). Repression of young, potentially active TEs appears especially crucial to maintain genome stability by inhibiting both transcription and recombination, which chiefly involves HP1α /H3K9me3-based heterochromatin in somatic cells (4, 56, 65) (Box2). As the most prominent chromatin marker in the B compartment is precisely the H3K9me3 mark (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The A and B regions may be further divided into subdomains that constitute the elementary unit of unfolding/refolding of the genome (3). In vertebrates, these domains are called topologically associated domains (TADs) and are often delimited by boundary elements associated with DNA-binding factors, and in a high proportion of cases the transcription factor (TF) CTCF (4, 5). In a living cell, the chromatin fiber is pervasively set in motion due to the action of “active effectors” (6, 7), in particular cohesin rings that relentlessly extrude DNA, forming chromatin loops that enlarge until the cohesin ring detaches or arrests.…”

Section: Introductionmentioning

confidence: 99%

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ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet,

Hulo,

Mourad

et al. 2023

Preprint

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SUMMARYThere is a growing awareness that repeat sequences (RepSeq) - the main constituents of the human genome - are also prime players in its organization. Here we propose that the genome should be envisioned as a supersystem with three main subsystems, each composed of functionally redundant, cooperating elements. We define herein ProA and ProB RepSeqs as sequences that promote either the A/euchromatin or the B/heterochromatin compartment. ProA and ProB RepSeqs shape A/B partitioning, such that the relative proportions of ProA and ProB RepSeqs determine the propensity of a chromosome segment to adopt either an A or a B configuration. In human, core ProA RepSeqs are essentially made of Alu elements, whereas core ProB RepSeqs consist of young L1 and some Endogenous Retroviruses (ERVs) as well as a panel of AT-rich microsatellites and pericentromeric and telomeric satellites. Additionally, RepSeqs with more indefinite character and, importantly, their derivatives known as “transcriptional enhancers”, can shift between ProA and ProB functions and thus act to open or close specific chromatin domains depending on the cellular context. In this framework, genes and their promoters appear as a special class of RepSeqs that, in their active, transcribed state, reinforce the openness of their surroundings. Molecular mechanisms involve cooperativity between ProB elements, presumably underpinned by the condensate-like properties of heterochromatin, which ProA elements oppose in several ways. We provide strong arguments that altered CpG methylation patterns in cancer including a marked loss in the B compartment, result primarily from a global imbalance in the process of CpG methylation and its erasure. Our results suggest that the resulting altered methylation and impaired function of ProB RepSeqs globally weaken the B compartment, rendering it more plastic, which in turn may confer fate plasticity to the cancer cell.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet,

Hulo,

Mourad

et al. 2023

Preprint

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“…3D chromatin structure and genome folding are organized at different scales of genomic length [ 1 , 15 , 19–21 , 31–35 ], which at least include (i) segregation of large mega-base (Mb)-long regions into active (type A) and inactive (type B) compartments [ 1 ]; (ii) formation of sub-Mb domains termed Topologically Associating Domains (TADs), which have a median size of approximately 880 kilobase (kb) in mouse embryonic stem cells (ESCs) [ 3 ]; (iii) smaller compartmental domains, sometimes referred to as nested TADs or sub-TADs, that span over a size of a few to dozens of kb region and can cover one to several genes [ 4 , 17 , 19 , 31 , 35 ]; and (iv) chromatin loops such as long-range enhancer–promoter interactions [ 34–36 ]. Chromosomal regions that fall into the same compartment type (type A or B) interact with each other more frequently than those that do not.…”

Section: Introductionmentioning

confidence: 99%

Through the lens of phase separation: intrinsically unstructured protein and chromatin looping

Cai

Wang

2023

Nucleus

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The establishment, maintenance and dynamic regulation of three-dimensional (3D) chromatin structures provide an important means for partitioning of genome into functionally distinctive domains, which helps to define specialized gene expression programs associated with developmental stages and cell types. Increasing evidence supports critical roles for intrinsically disordered regions (IDRs) harbored within transcription factors (TFs) and chromatin-modulatory proteins in inducing phase separation, a phenomenon of forming membrane-less condensates through partitioning of biomolecules. Such a process is also critically involved in the establishment of high-order chromatin structures and looping. IDR- and phase separation-driven 3D genome (re)organization often goes wrong in disease such as cancer. This review discusses about recent advances in understanding how phase separation of intrinsically disordered proteins (IDPs) modulates chromatin looping and gene expression.

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“…The three-dimensional (3D) organization of the genome is essential in facilitating fundamental processes which occur in the cell nucleus including, transcriptional regulation, DNA damage and replication ( McCord et al, 2020 ). Over the last 20 years, chromosome conformation capture (3C) techniques have been widely used to identify and estimate the frequency of interaction of multiple genomic loci in the genome ( Dekker et al, 2002 ; Phillips-Cremins et al, 2013 ; Hansen et al, 2018 ; Haws et al, 2022 ). In 3C methodology, restriction enzyme digestion followed by re-ligation of cross-linked chromatin in the nucleus of a cell, allows to detect the spatial vicinity between DNA sequences ( de Wit and de Laat, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Chromosome conformation capture approaches to investigate 3D genome architecture in Ankylosing Spondylitis

et al. 2023

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Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis of the spine exhibiting a strong genetic background. The mechanistic and functional understanding of the AS-associated genomic loci, identified with Genome Wide Association Studies (GWAS), remains challenging. Chromosome conformation capture (3C) and derivatives are recent techniques which are of great help in elucidating the spatial genome organization and of enormous support in uncover a mechanistic explanation for disease-associated genetic variants. The perturbation of three-dimensional (3D) genome hierarchy may lead to a plethora of human diseases, including rheumatological disorders. Here we illustrate the latest approaches and related findings on the field of genome organization, highlighting how the instability of 3D genome conformation may be among the causes of rheumatological disease phenotypes. We suggest a new perspective on the inclusive potential of a 3C approach to inform GWAS results in rheumatic diseases. 3D genome organization may ultimately lead to a more precise and comprehensive functional interpretation of AS association, which is the starting point for emerging and more specific therapies.

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3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome

Cited by 24 publications

References 172 publications

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Through the lens of phase separation: intrinsically unstructured protein and chromatin looping

Chromosome conformation capture approaches to investigate 3D genome architecture in Ankylosing Spondylitis

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