Ultra high-throughput whole-genome methylation sequencing reveals trajectories in precancerous polyps to early colorectal adenocarcinoma

Lee, Hayan; Krieger, Gat; Clark, Tyson A.; Khan, Aziz; Hanson, Casey; Zhu, Yizhou; Bararpour, Nasim; Horning, Aaron M.; Esplin, Edward D.; Nevins, Stephanie; Weimer, Annika K.; Meiri, Eti; Gilad, Shlomit; Schwessinger, Benjamin; Lebanony, Danit; Iremadze, Nika; Oberstraas, Florian; Jaimovich, Ariel; Greenleaf, William J.; Ford, Jim M.; Lipson, Doron; Shipony, Zohar; Snyder, M

doi:10.1101/2022.05.30.494076

“…To investigate the possible underlying mechanism(s) of CRE interaction loss, we performed 23 bulk ATAC seq and incorporated 21 EM seq from a separate study 35 for the colon tissues from the same patients examined by mHi-C with high sample overlap (23/33 samples; Figure 1A ). Aligning the methylation profile with stripe strengths in mucosa, we found they were significantly inversely correlated (r = −0.52).…”

Section: Resultsmentioning

confidence: 99%

“…The Enzymatic Methyl seq was performed as described 35 . Libraries were constructed by using the NEBNext Enzymatic Methyl-seq Kit (NEB), following manufacturer’s guidance.…”

Section: Methodsmentioning

confidence: 99%

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis

Zhu

¹

,

Lee

²

,

Weimer

³

et al. 2022

Preprint

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Although 3D genome architecture is essential for long-range gene regulation, the significance of distal regulatory chromatin contacts is challenged by recent findings of low correlation between contact propensity and gene expression. To better understand the role of long-range interactions between distal regulatory elements during the early transformation from healthy colon to colorectal cancer, here we performed high resolution chromatin conformation capture for 33 samples including non-neoplastic mucosa, adenomatous polyps and adenocarcinomas, mostly from Familial Adenomatous Polyposis (FAP) patients. We identified hundreds of thousands of chromatin micro-structures, such as architectural stripes and loops, which originated from active cis-regulatory elements. Surprisingly, these structures progressively decayed throughout cancer progression, particularly at promoters. Meta-analyses revealed that this decay was independent of alterations in DNA methylation and chromatin accessibility. Interestingly, the degree of interaction loss was poorly correlated with gene expression changes. Instead, genes whose expression were disproportionately lower and higher than their relative promoter interaction in mucosa shifted their expression in polyps and adenocarcinomas to yield a more direct relationship between strength of interaction and gene expression. Our work provides the first high resolution 3D conformation maps during early cancer formation and progression, and provides novel insights into transcriptional readouts associated with fine-scale chromatin conformation alterations.

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“…The properties of methylation make it an attractive front-line epigenetic assay. Though sequencing cost is a major limitation, this issue is being rapidly addressed through technological innovation [17].…”

Section: Segmentation Retains Salient Genomic Featuresmentioning

confidence: 99%

A unified hypothesis-free feature extraction framework for diverse epigenomic data

Balcı

¹

,

Chikina

²

2023

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Motivation: Epigenetic assays using next-generation sequencing (NGS) have furthered our understanding of the functional genomic regions and the mechanisms of gene regulation. However, a single assay produces billions of data represented by nucleotide resolution signal tracks. The signal strength at a given nucleotide is subject to numerous sources of technical a biological noise and thus conveys limited information about the underlying biological state. In order to draw biological conclusions, data is typically summarized into higher order patterns. Numerous specialized algorithms for summarizing epigenetic signal have been proposed and include methods for peak calling or finding differentially methylated regions. A key unifying principle underlying these approaches is that they all leverage the strong prior that signal must be locally consistent. Results: We propose L0 segmentation as a universal framework for extracting locally coherent signals for diverse epigenetic sources. L0 serves to both compress and smooth the input signal by approximating it as piece-wise constant. We implement a highly scalable L0 segmentation with additional loss functions designed for NGS epigenetic data types including Poisson loss for single tracks and binomial loss for methylation/coverage data. In contrast to the widely used L1 segmentation problem, known as fused lasso, the L0 solution does not induce global attenuation and is able to capture the salient features of the data over a wide range of compression values. Finally, we show that L0 segmentation can be used as an effective prior inside other machine learning models, such as matrix factorization.

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“…To investigate the possible underlying mechanism(s) of CRE interaction loss, we performed 23 bulk ATAC seq and incorporated 21 EM seq from a separate study 35 for the colon tissues from the same patients examined by mHi-C with high sample overlap (23/33 samples; Figure 1A). Aligning the methylation pro le with stripe strengths in mucosa, we found they were signi cantly inversely correlated (r = -0.52).…”

Section: Dna Methylation and Chromatin Accessibility Do Not Fully Exp...mentioning

confidence: 99%

“…Enzymatic Methyl seq was performed as described 35 . Libraries were constructed by using the NEBNext Enzymatic Methyl-seq Kit (NEB), following manufacturer's guidance.…”

Section: Em Seqmentioning

confidence: 99%

Global loss of fine-scale chromatin architecture and rebalancing of gene expression during early colorectal cancer development

Snyder

¹

,

Zhu

²

,

Lee

³

et al. 2022

Preprint

Self Cite

0

View full text Add to dashboard Cite

Although 3D genome architecture is essential for long-range gene regulation, the significance of distal regulatory chromatin contacts is challenged by recent findings of low correlation between contact propensity and gene expression. To better understand the role of long-range interactions between distal regulatory elements during the early transformation from healthy colon to colorectal cancer, here we performed high resolution chromatin conformation capture for 33 samples including non-neoplastic mucosa, adenomatous polyps and adenocarcinomas, mostly from Familial Adenomatous Polyposis (FAP) patients. We identified hundreds of thousands of chromatin micro-structures, such as architectural stripes and loops, which originated from active cis-regulatory elements. Surprisingly, these structures progressively decayed throughout cancer progression, particularly at promoters. Meta-analyses revealed that this decay was independent of alterations in DNA methylation and chromatin accessibility. Interestingly, the degree of interaction loss was poorly correlated with gene expression changes. Instead, genes whose expression were disproportionately lower and higher than their relative promoter interaction in mucosa shifted their expression in polyps and adenocarcinomas to yield a more direct relationship between strength of interaction and gene expression. Our work provides the first high resolution 3D conformation maps during early cancer formation and progression, and provides novel insights into transcriptional readouts associated with fine-scale chromatin conformation alterations.

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Ultra high-throughput whole-genome methylation sequencing reveals trajectories in precancerous polyps to early colorectal adenocarcinoma

Cited by 6 publications

References 49 publications

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis

A unified hypothesis-free feature extraction framework for diverse epigenomic data

Global loss of fine-scale chromatin architecture and rebalancing of gene expression during early colorectal cancer development

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