Organization of the Mitotic Chromosome

Naumova, Natalia; Imakaev, Maxim; Fudenberg, Geoffrey; Ye, Zhan; Lajoie, Bryan R.; Mirny, Leonid A.; Dekker, Job

doi:10.1126/science.1236083

Cited by 940 publications

(1,231 citation statements)

References 49 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%

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%

Two independent modes of chromatin organization revealed by cohesin removal

Schwarzer

Abdennur

Goloborodko

et al. 2017

Nature

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“…However, the initiation and progression of replication, followed by the segregation of the sister chromatids (SCs) into daughter cells, is expected to modify the genome higher‐order organization. Recent studies have unveiled cell‐cycle stage‐specific genome‐wide topological variations in bacteria, yeast, fly, and mammals (Naumova et al , 2013; Guidi et al , 2015; Marbouty et al , 2015; Hug et al , 2017). As expected, in all species the largest reorganization transition is associated with SC condensation, a fundamental process occurring concomitantly to their individualization, and facilitating their proper segregation.…”

Section: Introductionmentioning

confidence: 99%

“…While Hi‐C studies on mammalian and drosophila cells have confirmed this compaction change and provided important insights on the organization of mitotic chromosomes’ internal structure (Naumova et al , 2013; Hug et al , 2017), no comprehensive analysis of the 4D dynamics of the chromosomes during an entire eukaryotic cell cycle has been achieved. To explore new chromosomal structural features over the cell cycle progression, we analyzed the internal folding and overall organization of S. cerevisiae genome over 15 synchronized time points and the role of cohesin and condensin using Hi‐C (Dekker et al , 2002; Lieberman‐Aiden et al , 2009).…”

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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“…During mitosis, the chromosomes markedly condense, RNA polymerase is excluded from the chromatin, and transcription ceases. Recent chromosome conformation capture studies show that the three-dimensional partitioning of genomic domains in interphase is almost completely lost during mitosis (Naumova et al 2013). During mitotic exit, such domains are re-established, RNA polymerase re-engages the chromatin, and the entire genome becomes transcriptionally activated in a manner that faithfully recapitulates the prereplicated state of the cell (Egli et al 2008).…”

Section: Pioneer Factors As Bookmarking Factors In Mitosismentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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Organization of the Mitotic Chromosome

Cited by 940 publications

References 49 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

Pioneer transcription factors in cell reprogramming

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