Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments DOI Creative Commons
Viraat Y. Goel, Miles K. Huseyin, Anders S. Hansen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: July 14, 2022

Although enhancers are central to the regulation of mammalian gene expression, mechanisms underlying Enhancer-Promoter (E-P) interactions remain unclear. Chromosome conformation capture (3C) methods effectively large-scale 3D genome structure but struggle achieve depth necessary resolve fine-scale E-P interactions. Here, we develop Region Capture Micro-C (RCMC) by combining MNase-based 3C with a tiling region-capture approach and generate deepest maps reported thus far only modest sequencing. By applying RCMC in mouse embryonic stem cells reaching genome-wide equivalent ∼200 billion unique contacts, reveals previously unresolvable patterns highly nested focal interactions, which term microcompartments. Microcompartments frequently connect promoters largely robust loss loop extrusion inhibition transcription. We therefore propose that many form through compartmentalization mechanism, may explain why acute cohesin depletion modestly affects global expression.

Language: Английский

Roles of transposable elements in the regulation of mammalian transcription DOI
Raquel Fueyo, Julius Judd, Cédric Feschotte

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(7), P. 481 - 497

Published: Feb. 28, 2022

Language: Английский

Citations

268
Characterizing cis-regulatory elements using single-cell epigenomics DOI
Sebastian Preißl, Kyle J. Gaulton, Bing Ren

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 24(1), P. 21 - 43

Published: July 15, 2022

Language: Английский

Citations

153
Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments DOI
Viraat Y. Goel, Miles K. Huseyin, Anders S. Hansen

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(6), P. 1048 - 1056

Published: May 8, 2023

Language: Английский

Citations

136
Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF DOI Creative Commons
Abrar Aljahani, Hua Peng, Magdalena A. Karpińska

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 19, 2022

Abstract Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated cohesin CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale to what extent fine-scale regulatory interactions depend on extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, has enabled us generate the most detailed local interaction data date (20 bp resolution) precisely investigate effects of CTCF depletion architecture. Our reveal that cis -regulatory elements have distinct internal nano-scale structures, insulation dependent CTCF, but independent cohesin. In contrast, find causes a subtle reduction in longer-range enhancer-promoter can cause rewiring contacts. Together, our show not essential for interactions, contributes their robustness specificity precise regulation gene expression.

Language: Английский

Citations

95
Diverse silent chromatin states modulate genome compartmentalization and loop extrusion barriers DOI Creative Commons
George Spracklin, Nezar Abdennur, Maxim Imakaev

et al.

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 30(1), P. 38 - 51

Published: Dec. 22, 2022

Abstract The relationships between chromosomal compartmentalization, chromatin state and function are poorly understood. Here by profiling long-range contact frequencies in HCT116 colon cancer cells, we distinguish three silent states, comprising two types of heterochromatin a enriched for H3K9me2 H2A.Z that exhibits neutral three-dimensional interaction preferences which, to our knowledge, has not previously been characterized. We find marked H3K9me3, HP1α HP1β correlates with strong compartmentalization. demonstrate disruption DNA methyltransferase activity greatly remodels genome compartmentalization whereby domains lose H3K9me3-HP1α/β binding acquire the neutrally interacting while retaining late replication timing. Furthermore, show is permissive loop extrusion cohesin but refractory CTCF binding. Together, work reveals dynamic structural organizational diversity portion establishes connections regulation chromosome organization, including an interplay methylation, extrusion.

Language: Английский

Citations

83
Super-enhancers include classical enhancers and facilitators to fully activate gene expression DOI Creative Commons
Joseph Blayney, Helena S. Francis, Alexandra Rampasekova

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5826 - 5839.e18

Published: Dec. 1, 2023

Super-enhancers are compound regulatory elements that control expression of key cell identity genes. They recruit high levels tissue-specific transcription factors and co-activators such as the Mediator complex contact target gene promoters with frequency. Most super-enhancers contain multiple constituent elements, but it is unclear whether these have distinct roles in activating expression. Here, by rebuilding endogenous multipartite α-globin super-enhancer, we show contains bioinformatically equivalent functionally element types: classical enhancers facilitator elements. Facilitators no intrinsic enhancer activity, yet their absence, unable to fully upregulate Without facilitators, exhibit reduced recruitment, RNA transcription, enhancer-promoter interactions. interchangeable display functional hierarchy based on position within a enhancer. thus play an important role potentiating activity ensuring robust activation

Language: Английский

Citations

81
Enhancer–promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness DOI
Shreeta Chakraborty,

Nina Kopitchinski,

Zhenyu Zuo

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 280 - 290

Published: Jan. 30, 2023

Language: Английский

Citations

76
Validation of the new EPIC DNA methylation microarray (900K EPIC v2) for high-throughput profiling of the human DNA methylome DOI Creative Commons
Aleix Noguera‐Castells, Carlos A. García‐Prieto,

Damiana Álvarez‐Errico

et al.

Epigenetics, Journal Year: 2023, Volume and Issue: 18(1)

Published: March 5, 2023

DNA methylation, one of the best characterized epigenetic marks in human genome, plays a pivotal role gene transcription regulation and other biological processes humans. On top that, methylome undergoes profound changes cancer disorders. However, large-scale population-based studies are limited by high costs need for considerable expertise data analysis whole-genome bisulphite-sequencing methodologies. Following success EPIC methylation microarray, newly developed Infinium HumanMethylationEPIC version 2.0 (900K v2) is now available. This new array contains more than 900,000 CpG probes covering genome excluding masked from previous version. The 900K v2 microarray adds 200,000 extra cis-regulatory regions such as enhancers, super-enhancers CTCF binding regions. Herein, we have technically biologically validated to show its reproducibility consistency among technical replicates with extracted FFPE tissue. In addition, hybridized primary normal tumoural tissues cell lines different sources tested robustness when analysing profiles. validation highlights improvements offered demonstrates versatility this updated tool characterizing health disease.

Language: Английский

Citations

62
Transposable elements in mammalian chromatin organization DOI
Heather A. Lawson, Yonghao Liang, Ting Wang

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(10), P. 712 - 723

Published: June 7, 2023

Language: Английский

Citations

58
The Mediator complex regulates enhancer-promoter interactions DOI Creative Commons

Shyam Ramasamy,

Abrar Aljahani, Magdalena A. Karpińska

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(7), P. 991 - 1000

Published: July 1, 2023

Abstract Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target promoters. However, the molecular mechanisms by which interactions promoters are formed not well understood. Here, we investigate function of Mediator complex in regulation enhancer-promoter interactions, combining rapid protein depletion high-resolution MNase-based chromosome conformation capture approaches. We show that leads to reduced interaction frequencies, associated with a strong decrease expression. In addition, find increased CTCF-binding sites upon depletion. These changes chromatin architecture redistribution Cohesin on reduction occupancy at enhancers. Together, our results indicate complexes contribute provide insights into communication is regulated.

Language: Английский

Citations

56