A Phase Separation Model for Transcriptional Control

Hnisz, Denes; Shrinivas, Krishna; Young, Richard A.; Chakraborty, Arup K.; Sharp, Phillip A.

doi:10.1016/j.cell.2017.02.007

Cited by 1,453 publications

(1,391 citation statements)

References 84 publications

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“…The accuracy achieved by using our energy landscape model in predicting the effects of compartmentalization, as seen by Hi-C and 3D FISH, supports the plausibility of microphase separation being the physical process driving compartmentalization in chromosomes (17,(34)(35)(36) (Fig. 4).…”

Section: Significancementioning

confidence: 69%

De Novo Prediction of Human Chromosome Structures: Epigenetic Marking Patterns Encode Genome Architecture

Pierro

Cheng

Aiden

et al. 2018

Biophysical Journal

129

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Inside the cell nucleus, genomes fold into organized structures that are characteristic of cell type. Here, we show that this chromatin architecture can be predicted de novo using epigenetic data derived from chromatin immunoprecipitation-sequencing (ChIP-Seq). We exploit the idea that chromosomes encode a 1D sequence of chromatin structural types. Interactions between these chromatin types determine the 3D structural ensemble of chromosomes through a process similar to phase separation. First, a neural network is used to infer the relation between the epigenetic marks present at a locus, as assayed by ChIP-Seq, and the genomic compartment in which those loci reside, as measured by DNA-DNA proximity ligation (Hi-C). Next, types inferred from this neural network are used as an input to an energy landscape model for chromatin organization [Minimal Chromatin Model (MiChroM)] to generate an ensemble of 3D chromosome conformations at a resolution of 50 kilobases (kb). After training the model, dubbed Maximum Entropy Genomic Annotation from Biomarkers Associated to Structural Ensembles (MEGABASE), on odd-numbered chromosomes, we predict the sequences of chromatin types and the subsequent 3D conformational ensembles for the even chromosomes. We validate these structural ensembles by using ChIP-Seq tracks alone to predict Hi-C maps, as well as distances measured using 3D fluorescence in situ hybridization (FISH) experiments. Both sets of experiments support the hypothesis of phase separation being the driving process behind compartmentalization. These findings strongly suggest that epigenetic marking patterns encode sufficient information to determine the global architecture of chromosomes and that de novo structure prediction for whole genomes may be increasingly possible.epigenetics | machine learning | energy landscape theory | genomic architecture | Hi-C I n the nucleus of eukaryotic cells, the 1D information of the genome is organized in three dimensions (1, 2). It is increasingly evident that genomic spatial organization is a key element of transcriptional regulation (1, 3, 4). During interphase, the 3D arrangement of chromatin brings into close spatial proximity sections of DNA separated by great genomic distance, introducing interactions between genes and regulatory elements. These folding patterns are cell type-specific (5, 6), and their disruption can lead to disease (7-10).The use of high-resolution contact mapping experiments (Hi-C) has revealed that, at the large scale, genome structure is dominated by the segregation of human chromatin into compartments. Initial analysis of Hi-C experiments revealed that loci typically exhibited one of two long-range contact patterns, suggesting the presence of two spatial neighborhoods, dubbed the A and B compartments (11). Subsequently, higher resolution experiments have shown the presence of six distinct long-range patterns, indicating the presence of six subcompartments (A1, A2, B1, B2, B3, and B4) in human lymphoblastoid cells (GM12878) (6). The compartmentalization o...

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Section: Significancementioning

confidence: 69%

De Novo Prediction of Human Chromosome Structures: Epigenetic Marking Patterns Encode Genome Architecture

Pierro

Cheng

Aiden

et al. 2018

Biophysical Journal

129

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“…These quantities cannot be derived from the empirical conformation capture data and requires complementary method, such as single particle tracking [24,25]. The present analysis reveals also the statistics of complex matter at the transition point between liquid and gel [26,27] and also how transcriptional bursting dynamics is modulated by the random architecture of chromatin sub-organization. To validate the heterogeneous RCL model, we reconstructed multiple TAD reorganization during three successive stages of cell differentiation: mouse embryonic stem cell (ESC), neuronal precursor cells (NPC) and mouse embryonic fibroblasts (MEF).…”

Section: Discussionmentioning

confidence: 85%

Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers

Shukron

Piras

Noordermeer

et al. 2017

Preprint

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Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating domains (TADs). The folding hierarchy of the TADs and their internal organization is highly dynamic through cellular differentiation, where structural changes within and between TADs are correlated with gene activation and silencing. How these changes in chromatin conformation is correlated with gene regulation can be revealed by polymer models. Here we introduce a heterogeneous randomly cross-linked (RCL) polymer model that accounts for multiple interacting TADs. We study how connectivity within and between TADs affects chromatin organization and dynamics. Closed formula for the steady-state encounter probability within and between TADs indicate how cross-links across TADs affect TAD size and the dynamics of the chromatin. We apply the present polymer model to characterize the degree of compaction and show how secondary structures such as meta-TADs can be detected in Hi-C data. Finally, we apply the present approach to reconstruct high-order TAD organization due to inter-TAD connectivity for three TADs obtained from chromosomal capture data for the mammalian X chromosome during three successive stages of differentiation.

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“…Although the small size and compact nature of these transcription sites means that their structural details have yet to be observed directly, the possibility that miniature nuclear bodies form at each active gene has recently been considered (Herzel et al 2017). Moreover, theoretical considerations of transcriptional regulation have led to the suggestion that super enhancers reflect the formation of compartments involving transcriptional regulators, nascent transcripts, and other chromatin components (Hnisz et al 2017). …”

Section: Discussionmentioning

confidence: 99%

“…The other deals with the physical and functional organization of the interchromatin space, a prominent feature of which is the presence of a variety of nuclear bodies that are now thought to reflect the formation of liquid-liquid phase-separated compartments (Mao et al 2011; Zhu and Brangwynne 2015). Indeed it has recently been suggested that both of these organizational principals could be in operation at sites of RNA polymerase II (pol II) transcription (Hnisz et al 2017). However, many questions still remain about the formation and dynamics of individual loop structures and the detailed structure and organization of transcription sites in living cells.…”

Section: Introductionmentioning

confidence: 99%

Imaging the dynamics of transcription loops in living chromosomes

Morgan

2018

Chromosoma

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When in the lampbrush configuration, chromosomes display thousands of visible DNA loops that are transcribed at exceptionally high rates by RNA polymerase II (pol II). These transcription loops provide unique opportunities to investigate not only the detailed architecture of pol II transcription sites but also the structural dynamics of chromosome looping, which is receiving fresh attention as the organizational principle underpinning the higher-order structure of all chromosome states. The approach described here allows for extended imaging of individual transcription loops and transcription units under conditions in which loop RNA synthesis continues. In intact nuclei from lampbrush-stage Xenopus oocytes isolated under mineral oil, highly specific targeting of fluorescent fusions of the RNA-binding protein CELF1 to nascent transcripts allowed functional transcription loops to be observed and their longevity assessed over time. Some individual loops remained extended and essentially static structures over time courses of up to an hour. However, others were less stable and shrank markedly over periods of 30–60 min in a manner that suggested that loop extension requires continued dense coverage with nascent transcripts. In stable loops and loop-derived structures, the molecular dynamics of the visible nascent RNP component were addressed using photokinetic approaches. The results suggested that CELF1 exchanges freely between the accumulated nascent RNP and the surrounding nucleoplasm, and that it exits RNP with similar kinetics to its entrance. Overall, it appears that on transcription loops, nascent transcripts contribute to a dynamic self-organizing structure that exemplifies a phase-separated nuclear compartment.Electronic supplementary materialThe online version of this article (10.1007/s00412-018-0667-8) contains supplementary material, which is available to authorized users.

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A Phase Separation Model for Transcriptional Control

Cited by 1,453 publications

References 84 publications

De Novo Prediction of Human Chromosome Structures: Epigenetic Marking Patterns Encode Genome Architecture

De Novo Prediction of Human Chromosome Structures: Epigenetic Marking Patterns Encode Genome Architecture

Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers

Imaging the dynamics of transcription loops in living chromosomes

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