The 3D Genome as Moderator of Chromosomal Communication

Dekker, Job; Mirny, Leonid A.

doi:10.1016/j.cell.2016.02.007

Cited by 852 publications

(776 citation statements)

References 123 publications

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“…2e) or with up- and down-regulated transcription (Extended Data Figure 5c). This major reorganization of chromatin architecture is also reflected in the curves of contact frequency P(s) as a function of genomic distance s 3,29 . In control samples, like in other mammalian cells 14,15 , P(s) curve has two regimes: a more shallow decay for s<200Kb ( P(s)~s −0.7 ), and a steeper scaling for 200Kb < s < 3Mb ( P(s)~s −1.2 ).…”

Section: Disappearance Of Tads and Peaksmentioning

confidence: 93%

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Two independent modes of chromatin organization revealed by cohesin removal

Schwarzer

Abdennur

Goloborodko

et al. 2017

Nature

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Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-large active and inactive compartments, and partitioning into sub-megabase domains (TADs). Yet, it remains unclear how these layers of organization form, interact with one another and impact genome functions. Here, we show that deletion of the cohesin-loading factor Nipbl, in mouse liver, leads to a dramatic reorganization of chromosomal folding. TADs and associated peaks vanish globally, even in the absence of transcriptional changes. In contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the interplay of two independent mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; 2) cohesin-dependent formation of TADs, possibly by loop extrusion, which contributes to guide distant enhancers to their target genes.

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Section: Disappearance Of Tads and Peaksmentioning

confidence: 93%

“…The three-dimensional organization of chromosomes is tightly related to their biological function 1–3 . Hi-C maps have revealed key features of the 3D organization of metazoan chromosomes, including compartmentalization, TADs, and interaction peaks 4,5 (Extended Data Figure 1).…”

mentioning

confidence: 99%

Two independent modes of chromatin organization revealed by cohesin removal

Schwarzer

Abdennur

Goloborodko

et al. 2017

Nature

Self Cite

1,054

114

1,115

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“…The chromosomes of prokaryotes and eukaryotes display multiple levels of hierarchical organization, whose dynamic changes influence or regulate metabolic processes including gene expression and DNA replication and repair (Taddei & Gasser, 2012; Wang et al , 2013; Dekker & Mirny, 2016). The improper coordination of chromosome condensation and segregation during the cell cycle can lead to important structural abnormalities and result in cell death or diseases such as cancer (Valton & Dekker, 2016).…”

Section: Introductionmentioning

confidence: 99%

Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle

et al. 2017

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Duplication and segregation of chromosomes involves dynamic reorganization of their internal structure by conserved architectural proteins, including the structural maintenance of chromosomes (SMC) complexes cohesin and condensin. Despite active investigation of the roles of these factors, a genome‐wide view of dynamic chromosome architecture at both small and large scale during cell division is still missing. Here, we report the first comprehensive 4D analysis of the higher‐order organization of the Saccharomyces cerevisiae genome throughout the cell cycle and investigate the roles of SMC complexes in controlling structural transitions. During replication, cohesion establishment promotes numerous long‐range intra‐chromosomal contacts and correlates with the individualization of chromosomes, which culminates at metaphase. In anaphase, mitotic chromosomes are abruptly reorganized depending on mechanical forces exerted by the mitotic spindle. Formation of a condensin‐dependent loop bridging the centromere cluster with the rDNA loci suggests that condensin‐mediated forces may also directly facilitate segregation. This work therefore comprehensively recapitulates cell cycle‐dependent chromosome dynamics in a unicellular eukaryote, but also unveils new features of chromosome structural reorganization during highly conserved stages of cell division.

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“…The billions of DNA bases in the eukaryotic genome must be efficiently packed to fit inside the micronsized nucleus and to perform necessary cellular functions including gene expression as well as DNA replication and repair [1][2][3]. Abnormal 3D packaging of chromatin may disrupt cellular homeostasis and lead to diseases [4,5].…”

Section: Introductionmentioning

confidence: 99%

Iteratively improving Hi-C experiments one step at a time

Golloshi

Sanders

McCord

2018

Preprint

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(250 words)The 3D organization of eukaryotic chromosomes affects key processes such as gene expression, DNA replication, cell division, and response to DNA damage. The genome-wide chromosome conformation capture (Hi-C) approach can characterize the landscape of 3D genome organization by measuring interaction frequencies between all genomic regions. Hi-C protocol improvements and rapid advances in DNA sequencing power have made Hi-C useful to diverse biological systems, not only to elucidate the role of 3D genome structure in proper cellular function, but also to characterize genomic rearrangements, assemble new genomes, and consider chromatin interactions as potential biomarkers for diseases. Yet, the Hi-C protocol is still complex and subject to variations at numerous steps that can affect the resulting data. Thus, there is still a need for better understanding and control of factors that contribute to Hi-C experiment success and data quality. Here, we evaluate recently proposed Hi-C protocol modifications as well as often overlooked variables in sample preparation and examine their effects on Hi-C data quality. We examine artifacts that can occur during Hi-C library preparation, including microhomology-based artificial template copying and chimera formation that can add noise to the downstream data. Exploring the mechanisms underlying Hi-C artifacts pinpoints steps that should be further optimized in the future. To improve the utility of Hi-C in characterizing the 3D genome of specialized populations of cells or small samples of primary tissue, we identify steps prone to DNA loss which should be optimized to adapt Hi-C to lower cell numbers.Keywords: Hi-C; chromosome conformation capture; 3D genome structure; high throughput sequencing Highlights: 3 to 5 bullet points (maximum 85 characters, including spaces, per bullet point)  Variability in Hi-C libraries can arise from early steps of cell preparation  Hi-C 2.0 changes to interaction capture steps also benefit 6-cutter libraries  Artificial molecule fusions can arise during end repair and PCR, increasing noise 

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The 3D Genome as Moderator of Chromosomal Communication

Cited by 852 publications

References 123 publications

Two independent modes of chromatin organization revealed by cohesin removal

Two independent modes of chromatin organization revealed by cohesin removal

Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle

Iteratively improving Hi-C experiments one step at a time

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