Cohesin: building loops, but not compartments

Haarhuis, Judith H.I.; Rowland, Benjamin D.

doi:10.15252/embj.201798654

Cited by 23 publications

(29 citation statements)

References 15 publications

(38 reference statements)

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“…While the key role of molecular motors in the cytoplasm is broadly appreciated (Phillips et al 2012) , there is now a growing appreciation for loop extrusion by SMC complexes as an active processes organizing and compacting chromatin in the nucleus (Nasmyth 2017;Haarhuis and Rowland 2017) . Analogous to the myriad uses for the contractile dynamics of active actin and tubulin networks, we hypothesize that the interphase loop extrusion has been repurposed for a variety of biological ends (Fudenberg et al 2016;Dekker and Mirny 2016) , including targeting VDJ recombination, and regulation of enhancer-promoter interactions.…”

Section: Discussionmentioning

confidence: 99%

Emerging Evidence of Chromosome Folding by Loop Extrusion

Fudenberg

Abdennur

Imakaev

et al. 2018

Preprint

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Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.

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Section: Discussionmentioning

confidence: 99%

Emerging Evidence of Chromosome Folding by Loop Extrusion

Fudenberg

Abdennur

Imakaev

et al. 2018

Preprint

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“…Cohesin-independent maintenance of Hi-C detectable A and B compartments was reported in several studies (reviewed in [22]). In line with only minor effects of cohesin depletion on gene expression [18], the present study underpins that mechanisms that direct the maintenance of individual RDs and their spatio-temporal order, as well as the spatial arrangement of higher order chromatin organization in the context of the ANC-INC model are also independent of cohesin and sufficient to instruct accurate reformation of these structures upon exit from mitosis into a subsequent cell cycle in the absence of cohesin.…”

Section: Discussionmentioning

confidence: 99%

“…Compartments, manifesting when chromatin intervals with common histone signatures co-localize [13], were retained and even strengthened, leading to the presence of compartment domains and even compartment loops (but no loop domains) in the treated cells [18]. Other studies, using different cell types and approaches for cohesin elimination yielded similar results [19–21], (reviewed in [22]).…”

Section: Introductionmentioning

confidence: 88%

“…HCT-116-RAD21-mAC cells were plated in 6 well plates with either complete media, or complete media with 500uM auxin (IAA) for 6 hours (as in [22]) or 28 hours (to enrich for post-mitotic cells with multilobulated nuclei). Cells were crosslinked with 1% formaldehyde directly on the plate for 10 minutes and then quenched with glycine.…”

Section: Methodsmentioning

confidence: 99%

“…All contact matrices used for further analysis were KR-normalized with Juicer. Comparison of compartment strengthening to histone modification clusters was done as in [22]. Histone modification data for 9 marks (H3K36me3, H3K27Ac, H3K4me1, H4K16Ac, H3K79me2, H2AZ, H4K20me3, H3K27me3, H3K9me3) generated from untreated and 6-hour treated cells in [22] was grouped into 6 clusters using k-means clustering.…”

Section: Methodsmentioning

confidence: 99%

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Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

Cremer

Brandstetter

Maiser

et al. 2019

Preprint

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43The human genome forms thousands of "contact domains", which are intervals of enhanced 44 contact frequency. Some, called "loop domains" are thought to form by cohesin-mediated loop 45 extrusion. Others, called "compartmental domains", form due to the segregation of active and 46 inactive chromatin into A and B compartments. Recently, Hi-C studies revealed that the 47 depletion of cohesin leads to the disappearance of all loop domains within a few hours, but 48 strengthens compartment structure. Here, we combine live cell microscopy, super-resolution 49 microscopy, Hi-C, and studies of replication timing to examine the longer-term consequences 50 of cohesin degradation in HCT-116 human colorectal carcinoma cells, tracking cells for up to 51 30 hours. Surprisingly, cohesin depleted cells proceed through an aberrant mitosis, yielding a 52 single postmitotic cell with a multilobulated nucleus. Hi-C reveals the continued disappearance 53 of loop domains, whereas A and B compartments are maintained. In line with Hi-C, microscopic 54 observations demonstrate the reconstitution of chromosome territories and chromatin 55 domains. An interchromatin channel system (IC) expands between chromatin domain clusters 56 and carries splicing speckles. The IC is lined by active chromatin enriched for RNA Pol II and 57 depleted in H3K27me3. Moreover, the cells exhibit typical early-, mid-, and late-DNA 58 replication timing patterns. Our observations indicate that the functional nuclear 59 compartmentalization can be maintained in cohesin depleted pre-and postmitotic cells.60 However, we find that replication foci -sites of active DNA synthesis -become physically 61 larger consistent with a model where cohesin dependent loop extrusion tends to compact 62 intervals of replicating chromatin, whereas their genomic boundaries are associated with 63 compartmentalization, and do not change.64 65 3 Abbreviations 66 3D FISH = 3D fluorescence in situ hybridization 67 3D SIM = 3D structured illumination microscopy 68 AID = auxin inducible degron 69 ANC / INC = active / inactive nuclear compartment 70 CT = chromosome territory 71 CD(C) = chromatin domain (cluster) 72 CTCF = CCCTC binding factor 73 DAPI = 4',6-diamidino-2-phenylindole 74 EdU = 5-Ethynyl-2'-deoxyuridine 75 Hi-C = chromosome conformation capturing combined with deep sequencing 76 IC = interchromatin compartment 77 MLN = multilobulated nucleus 78 NC = nucleosome cluster 79 PBS = phosphate buffered saline 80 PBST = phosphate buffered saline with 0.02% Tween 81 PR = perichromatin region 82 RD = replication domain 83 RL = replication labeling 84 TAD = topologically associating domain 85 86 109 strengthened, leading to the presence of compartment domains and even compartment loops110 (but no loop domains) in the treated cells [18]. Other studies, using different cell types and 111 approaches for cohesin elimination yielded similar results [19-21], (reviewed in [22]). 112Here, we study the longer-term consequences of cohesin depletion and its effects on 113 the higher order nuclear a...

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The Genomic Code: A Pervasive Encoding/Molding of Chromatin Structures and a Solution of the “Non‐Coding DNA” Mystery

Bernardi

2019

BioEssays

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Recent investigations have revealed 1) that the isochores of the human genome group into two super-families characterized by two different long-range 3D structures, and 2) that these structures, essentially based on the distribution and topology of short sequences, mold primary chromatin domains (and define nucleosome binding). More specifically, GC-poor, gene-poor isochores are low-heterogeneity sequences with oligo-A spikes that mold the lamina-associated domains (LADs), whereas GC-rich, gene-rich isochores are characterized by single or multiple GC peaks that mold the topologically associating domains (TADs). The formation of these "primary TADs" may be followed by extrusion under the action of cohesin and CTCF. Finally, the genomic code, which is responsible for the pervasive encoding and molding of primary chromatin domains (LADs and primary TADs, namely the "gene spaces"/"spatial compartments") resolves the longstanding problems of "non-coding DNA," "junk DNA," and "selfish DNA" leading to a new vision of the genome as shaped by DNA sequences. and its role on the structure of the genome. This review deals exactly with this problem and shows, on the basis of past [4][5][6] and recent [7][8][9][10] published findings, that there is a fundamental link between DNA structure and chromatin structure, the "genomic code," which involves the encoding and molding of chromatin structure. Furthermore, being pervasive in the genome, the genomic code solves old outstanding problems, such as the "non-coding DNA," "junk DNA," or "selfish DNA."A good starting point for this introduction is to recall three early observations that are the roots of the recent findings because they concern DNA conformation and its link with the distribution of short sequences in the genome. This will be done not merely for historical reasons but because of their relevance to the recent results under review. Fifty five years ago, it was found [11] that calf thymus DNA undergoes a reversible decrease in viscosity in the sub-melting temperature range, indicating a reversible change in the configuration of ≈35% GCpoor DNA molecules. Five years later, two approaches, developed in order to fractionate DNAs on the basis of composition, provided information on their 3D conformation and their shortsequence frequencies. The background of the first approach was the chromatography of proteins on hydroxyapatite, a type of calcium phosphate, which had been shown to separate phosphoproteins according to their phosphate levels. [12] When applied to DNA, this approach separated native from denatured DNA, a "collapsed" structure that is eluted at a lower phosphate molarity because it has less phosphates available for binding to the calcium of hydroxyapatite. [13] In 1968, the discovery was made that hydroxyapatite could also separate yeast nuclear DNA (38% GC) from mitochondrial DNAs (18% GC in wild-type cells down to 4% GC in different "petite" mutants), the latter of which are eluted at increasingly higher phosphate molarities. This is because, being increasin...

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Cohesin: building loops, but not compartments

Cited by 23 publications

References 15 publications

Emerging Evidence of Chromosome Folding by Loop Extrusion

Emerging Evidence of Chromosome Folding by Loop Extrusion

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

The Genomic Code: A Pervasive Encoding/Molding of Chromatin Structures and a Solution of the “Non‐Coding DNA” Mystery

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