Ultra-long-range interactions between active regulatory elements

Friman, Elias T; Flyamer, Ilya M.; Boyle, Shelagh; Bickmore, Wendy A.

doi:10.1101/2022.11.30.518557

Cited by 6 publications

(7 citation statements)

References 88 publications

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“…Long distance CpGs have also been recently proven to be putative biomarkers for subtype-independent breast cancer diagnosis [45]. With the recent finding on the importance of ultra-long-range interactions between regulatory elements [47], we are now prompted to re-imagine the role of long distance methylation marks on gene modulation. However, the challenge to extract novel biological insights from complex data using deep learning remains a daunting task [14].…”

Section: Discussionmentioning

confidence: 99%

mEthAE: an Explainable AutoEncoder for methylation data

Katz

Santos

Saccenti

et al. 2023

Preprint

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Despite the wealth of knowledge generated through epigenome-wide association studies our understanding of the relationships of CpG sites is still limited, as analysis of DNA methylation data remains difficult due its high dimensionality. To combat this problem, deep learning algorithms, such as autoencoders, are increasingly applied to capture the complex patterns and reduce dimensionality into latent space. We believe that the way an autoencoder groups together CpGs in its latent dimensions has biological meaning and might reveal novel insights regarding the relationship of CpGs. Therefore, in this work, we propose a chromosome-wise autoencoder for interpretable dimensionality reduction of methylation data (mEthAE). Our framework shows an impressive reduction in dimensions of up to 400-fold compared to the provided input, without compromising on reconstruction accuracy or predictive power in the latent space. Through our perturbation-based interpretability approach we revealed groups of CpGs which are highly connected across all latent dimensions (global CpGs) and were significantly more often reported in EWAS studies, indicating our interpretability method can successfully identify CpGs with biological relevance. In an attempt to gain a deeper understanding of the relationship between individual CpG sites, we focused on interpreting individual latent features and found that CpGs connected to a common feature do not share biological associations, correlation patterns, or are located in close proximity on the chromosome. We conclude that while there is evidence that the autoencoder does not group CpGs randomly, the logic behind the observed CpG relationships can not be delineated easily. With regards to the analyses done in this work, we believe that the autoencoder groups CpGs according to long range non-linear interaction patterns that lack characterisation in the current epigenetic research landscape.

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Section: Discussionmentioning

confidence: 99%

mEthAE: an Explainable AutoEncoder for methylation data

Katz

Santos

Saccenti

et al. 2023

Preprint

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“…We can exclude that these changes occur only indirectly via impacting enhancer function as they are observed at CTCF sites regardless of whether they reside within or outside enhancers (Extended Data Fig. 9b) 32,33 .…”

Section: Absence Of Bptf Impacts Long-range Chromatin Interactionsmentioning

confidence: 99%

Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF

Iurlaro,

Masoni,

Flyamer

et al. 2024

Nat Genet

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Catalytic activity of the imitation switch (ISWI) family of remodelers is critical for nucleosomal organization and DNA binding of certain transcription factors, including the insulator protein CTCF. Here we define the contribution of individual subcomplexes by deriving a panel of isogenic mouse stem cell lines, each lacking one of six ISWI accessory subunits. Individual deletions of subunits of either CERF, RSF, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to a strong reduction in chromatin accessibility and SNF2H ATPase localization around CTCF sites. This affects adjacent nucleosome occupancy and CTCF binding. At a group of sites with reduced chromatin accessibility, CTCF binding persists but cohesin occupancy is reduced, resulting in decreased insulation. These results suggest that CTCF binding can be separated from its function as an insulator in nuclear organization and identify a specific role for NURF in mediating SNF2H localization and chromatin opening at bound CTCF sites.

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“…However, individual loci can also show increasing enhancer–promoter distances during transcriptional activation and be robust to cis- regulatory perturbations [ 66 , 67 ]. This mechanistic variability implies that active regulatory sites can contact each other over long distances and that enhancer–promoter proximity can be temporally separated from their effects on transcription [ 68 ]. The clustering of multiple regulatory sites and gene loci together in a TC to increase transcriptional output and enhance co-regulation may underlie a fundamental mechanism of coordinating gene expression programs toward a specific functional outcome for the cell.…”

Section: Chromatin Adaptor Proteins Drive Condensate Formation For Re...mentioning

confidence: 99%

Transcriptional condensates and phase separation: condensing information across scales and mechanisms

Demmerle

Hao

Cai

2023

Nucleus

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Transcription is the fundamental process of gene expression, which in eukaryotes occurs within the complex physicochemical environment of the nucleus. Decades of research have provided extreme detail in the molecular and functional mechanisms of transcription, but the spatial and genomic organization of transcription remains mysterious. Recent discoveries show that transcriptional components can undergo phase separation and create distinct compartments inside the nucleus, providing new models through which to view the transcription process in eukaryotes. In this review, we focus on transcriptional condensates and their phase separation-like behaviors. We suggest differentiation between physical descriptions of phase separation and the complex and dynamic biomolecular assemblies required for productive gene expression, and we discuss how transcriptional condensates are central to organizing the three-dimensional genome across spatial and temporal scales. Finally, we map approaches for therapeutic manipulation of transcriptional condensates and ask what technical advances are needed to understand transcriptional condensates more completely.

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Ultra-long-range interactions between active regulatory elements

Cited by 6 publications

References 88 publications

mEthAE: an Explainable AutoEncoder for methylation data

mEthAE: an Explainable AutoEncoder for methylation data

Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF

Transcriptional condensates and phase separation: condensing information across scales and mechanisms

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