Loop stacking organizes genome folding from TADs to chromosomes

Hafner, Antonina; Park, Min Hee; Berger, Scott E.; Murphy, Sedona E.; Nora, Elphège P.; Boettiger, Alistair N.

doi:10.1016/j.molcel.2023.04.008

Cited by 42 publications

(20 citation statements)

References 72 publications

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“…Interestingly, MED1-occupied chromatin interactions spanning over 10 Mb exhibited comparable up-regulation and down-regulation (i.e., un-changed in general) (Fig. 5e), supporting the notion that these ultra-long-range, multi-TAD-spanning chromatin interactions are regulated by a distinct mechanism 51,52 . In line with reports that active transcription is associated with a less compacted chromatin architecture in yeast 16 and that Mediator (through its kinase module) helps to maintain less compacted chromatin architecture favorable for transcription 15 , our results suggest a transcription-permissive 3D chromatin microenvironment through which 6KR MED1 promotes gene activation.…”

Section: Discussionsupporting

confidence: 64%

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression

Lin,

Roeder,

Barrows

et al. 2024

Preprint

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With our current appreciation of the complexity of eukaryotic transcription, whose dysregulation drives diseases including cancer, it is becoming apparent that identification of key events coordinating multiple aspects of transcriptional regulation is of special importance. To elucidate how assembly of RNA polymerase II (Pol II) with Mediator complex preinitiation complexes (PICs) and formation of transcription-permissive 3D chromatin organization are coordinated, we studied MED1, a representative subunit of the Mediator complex that acts to establish functional preinitiation complexes (PICs) that forms biomolecular condensates through an intrinsically disordered region (IDR) to facilitate transcription, and is implicated in the function of estrogen receptor α (hereafter ER) in ER-positive breast cancer (ER+ BC) cells. We found that MED1 is acetylated at 6 lysines in its IDR and, further, that MCF7 ER+ BC cells in which endogenous MED1 is replaced by an ectopic 6KR (non-acetylatable) mutant (6KR cells) exhibit enhanced cell growth and elevated expression of MED1-dependent genes. These results indicate an enhanced function of 6KR MED1 that may be attributed to two mechanisms: (1) reorganized PIC assembly, as indicated by increased MED1 and Pol II, decreased MED17, and equivalent ERα occupancies on chromatin, particularly at active enhancers and promoters; (2) sub-TAD chromatin unfolding, as revealed by HiCAR (Hi-C on accessible regulatory DNA) analyses. Furthermore, in vitro assays demonstrate distinct physio-chemical properties of liquid-liquid phase separation (LLPS) for 6KR versus 6KQ MED1 IDRs, and for non-acetylated versus CBP-acetylated WT MED1 IDR fragments. Related, Pol II CTD heptads are sequestered in 6KR and control WT MED1 IDR condensates, but not 6KQ and CBP-acetylated WT MED1 IDR condensates. These findings, in conjunction with recent reports of PIC structures, indicate that MED1 coordinates reorganization of the PIC machinery and the rewiring of regional chromatin organization through acetylation of its IDR. This study leads to an understanding of how the transition in phase behavior of a transcription cofactor acts as a mechanistic hub integrating linear and spatial chromatin functions to support gene expression, and have potential therapeutic implications for diseases involving MED1/Mediator-mediated transcription control.

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Section: Discussionsupporting

confidence: 64%

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression

Lin,

Roeder,

Barrows

et al. 2024

Preprint

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“…The two opposing views on the importance of the mesoscale genome architecture for gene regulation may converge if the general genome folding patterns play a role only in certain cell types or only under specific environmental conditions. Consistent with this view, the depletion of CTCF or cohesin in mouse cells leads to increased cell-to-cell variability in gene transcription, which is not apparent from bulk population assays ( 149 , 150 ). Future experiments that combine genetic perturbations with cell-type–specific readouts are required to test this hypothesis.…”

Section: Linking Genome Architecture To Gene Regulationmentioning

confidence: 68%

The scales, mechanisms, and dynamics of the genome architecture

Lizana,

Schwartz

2024

Sci. Adv.

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Even when split into several chromosomes, DNA molecules that make up our genome are too long to fit into the cell nuclei unless massively folded. Such folding must accommodate the need for timely access to selected parts of the genome by transcription factors, RNA polymerases, and DNA replication machinery. Here, we review our current understanding of the genome folding inside the interphase nuclei. We consider the resulting genome architecture at three scales with a particular focus on the intermediate (meso) scale and summarize the insights gained from recent experimental observations and diverse computational models.

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“…Our model is consistent with experiments showing that interphase chromatin is largely unentangled (45). Furthermore, recent work observed more disordered chromatin organization and anomalous genomic contacts on genomic length scales of several Mbps upon cohesin degradation (62), indicating that cohesin regulates chromatin conformation in a wide range of genomic lengths.…”

Section: Discussionmentioning

confidence: 99%

Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression

Chan,

Rubinstein

2024

Preprint

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In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that chromatin adopts a compact structure with limited interpenetration between chromosomes and between chromosomal sections. We developed a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross over between two and four at contour lengths on the order of 30 kilo-base pairs (kbp). The anomalously high fractal dimension D=4 is due to the inability of extruded loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such that overlaps between TADs are reduced to less than 35% and increases the entanglement strand of chromatin by up to a factor of 50 to several Mega-base pairs. Furthermore, active loop extrusion couples cohesin motion to chromatin conformations formed by previously extruding cohesins and causes the mean square displacement of chromatin loci during lag times (Δt) longer than tens of minutes to be proportional to Δ t1/3. We validate our results with hybrid molecular dynamics - Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin, explaining the physical reason for TAD segregation and suppression of chromatin entanglements which contribute to efficient gene regulation.

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Loop stacking organizes genome folding from TADs to chromosomes

Cited by 42 publications

References 72 publications

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression

The scales, mechanisms, and dynamics of the genome architecture

Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression

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