Single‐cell Hi‐C bridges microscopy and genome‐wide sequencing approaches to study 3D chromatin organization

Ulianov, Sergey V.; Tachibana-Konwalski, Kikuë; Razin, Sergey V.

doi:10.1002/bies.201700104

Cited by 35 publications

(20 citation statements)

References 61 publications

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“…Therefore, to uncover higher‐order chromatin organization in zygotes, we used a list of loop loci identified in CH12‐LX cells (Rao et al , ). For Hi‐C data on low numbers of cells (Ulianov et al , ), loops and TADs are most visible when averaged over multiple positions (Flyamer et al , ) and normalized relative to control regions that are selected from random shifts of loop loci (Appendix Fig S1A). Using our approach, we found that these data support the presence of loops and TADs in eight‐cell, two‐cell, and even one‐cell embryos (Fig B; Appendix Fig S1B) and are in agreement with previous findings that TADs and loops become stronger with progressing development (Du et al , ; Ke et al , ).…”

Section: Resultsmentioning

confidence: 99%

A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

et al. 2017

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Fertilization triggers assembly of higher‐order chromatin structure from a condensed maternal and a naïve paternal genome to generate a totipotent embryo. Chromatin loops and domains have been detected in mouse zygotes by single‐nucleus Hi‐C (snHi‐C), but not bulk Hi‐C. It is therefore unclear when and how embryonic chromatin conformations are assembled. Here, we investigated whether a mechanism of cohesin‐dependent loop extrusion generates higher‐order chromatin structures within the one‐cell embryo. Using snHi‐C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that critically depend on Scc1‐cohesin and that are regulated in size and linear density by Wapl. Remarkably, we discovered distinct effects on maternal and paternal chromatin loop sizes, likely reflecting differences in loop extrusion dynamics and epigenetic reprogramming. Dynamic polymer models of chromosomes reproduce changes in snHi‐C, suggesting a mechanism where cohesin locally compacts chromatin by active loop extrusion, whose processivity is controlled by Wapl. Our simulations and experimental data provide evidence that cohesin‐dependent loop extrusion organizes mammalian genomes over multiple scales from the one‐cell embryo onward.

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Section: Resultsmentioning

confidence: 99%

A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

et al. 2017

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“…2E ). Both DNA FISH 3,9,36–39 and single-cell Hi-C 40,41 studies show that genome organization is highly variable between cells and that even strong Hi-C loop anchors only contact in a small subset of cells, arguing that a simultaneous “loop rosette” occurs very rarely in a single cell.…”

Section: Tads Are Formed By Cohesin and Tad Boundaries Are Defined Bymentioning

confidence: 99%

Recent evidence that TADs and chromatin loops are dynamic structures

Hansen

Cattoglio

Darzacq

et al. 2017

Nucleus

228

194

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Mammalian genomes are folded into spatial domains, which regulate gene expression by modulating enhancer-promoter contacts. Here, we review recent studies on the structure and function of Topologically Associating Domains (TADs) and chromatin loops. We discuss how loop extrusion models can explain TAD formation and evidence that TADs are formed by the ring-shaped protein complex, cohesin, and that TAD boundaries are established by the DNA-binding protein, CTCF. We discuss our recent genomic, biochemical and single-molecule imaging studies on CTCF and cohesin, which suggest that TADs and chromatin loops are dynamic structures. We highlight complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model. We discuss the limitations of each approach and conclude that in aggregate the available evidence argues against stable loops and supports a model where TADs are dynamic structures that continually form and break throughout the cell cycle.

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“…A given high‐resolution TAD is related to an average structure of millions of chromatin domains (CDs) with the same DNA sequence. Single cell Hi‐C can provide data on TADs, whose 3D structure can be more directly compared with the 3D structure of individual TADs studied by advanced microscopy, (for review, see References 70 and 73). The greatly reduced number of contacts, which can be identified within the nucleus of an individual cell, however, goes hand in hand with a loss of Hi‐C resolution.…”

Section: Spatial Organization Of Regulatory Sequences Determined By Hi‐cmentioning

confidence: 99%

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

Cremer

2019

Genes Chromosomes & Cancer

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Transcription regulatory elements (TREs) have been extensively studied on the biochemical level with respect to their interactions with transcription factors (TFs), other DNA segments, and larger protein complexes. In this review, we describe concepts and preliminary experimental evidence for positional changes of TREs within a dynamic, functional nuclear architecture. We suggest a multilayered shell‐like chromatin organization of chromatin domain clusters with increasing chromatin compaction levels from the periphery toward the interior with a decondensed transcriptionally active peripheral layer and compact repressed chromatin typically located in the interior. This model organization of nuclear architecture implies a differential accessibility of TFs to targets located in co‐aligned active and inactive nuclear compartments (ANC and INC). It is based on evidence that active, easily accessible chromatin (perichromatin region, PR) lines a network of channels (interchromatin compartment, IC) involved in nuclear import–export functions. The IC and PR constitute the ANC, whereas transcriptionally noncompetent chromatin with higher compactness is part of the likely less accessible INC. Preliminary experimental evidence shows an enrichment of active TREs in the ANC and of inactive TREs in the INC suggesting positional changes of TREs between the ANC and INC depending on changes in their functional state.

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Single‐cell Hi‐C bridges microscopy and genome‐wide sequencing approaches to study 3D chromatin organization

Cited by 35 publications

References 61 publications

A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

Recent evidence that TADs and chromatin loops are dynamic structures

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

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