BPscore: An Effective Metric for Meaningful Comparisons of Structural Chromosome Segmentations

Zaborowski, Rafał; Wilczyński, Bartek

doi:10.1089/cmb.2018.0162

Cited by 6 publications

(4 citation statements)

References 29 publications

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“…These observations are suggestive of different modes of dynamic changes in co-expression domains, with low SLE activity genomes characterized by DCE fragmentation and high activity ones featuring a redistribution of co-expression with increased percentages of expanded and emerged DCEs. This redistribution was also supported by a simple value measure of DCE pattern similarity, calculated with the implementation of BPscore (26), which showed that in spite of being comparable in genome coverage, the DCEs between high activity patients and healthy controls were radically different in terms of genomic localization (Supplementary Figure 2).…”

Section: Dces Are Dynamically Redistributed In Slementioning

confidence: 62%

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Panousis

Tektonidou

et al. 2020

Preprint

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Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. We developed a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). By implementing this method on gene expression data from a large SLE patient cohort, we identify significant diseaseassociated alterations in gene co-regulation patterns, which also correlate with the SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to DCEs of smaller size. High disease activity genomes display excessive spatial redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. Fragmentation and redistribution of gene coexpression patterns correlate with SLE-implicated biological pathways and clinically relevant endophenotypes such as kidney involvement. Notably, genes lying at the boundaries of split DCEs of low activity genomes are enriched in the interferon and other SLE susceptibility signatures, suggesting the implication of DCE fragmentation at early disease stages. Interrogation of promoter-enhancer interactions from various immune cell subtypes shows that a significant percentage of nested connections are disrupted by a DCE split or depletion in SLE genomes. Collectively, our results underlining an important role for genome organization in shaping gene expression in SLE, could provide valuable insights into disease pathogenesis and the mechanisms underlying disease flares. Significance Although widespread gene expression changes have been reported in Systemic LupusErythematosus (SLE), attempts to link gene deregulation with genome structure have been lacking. Through a computational framework for the segmentation of gene expression data, we reveal extensive fragmentation and reorganization of gene co-regulation domains in SLE, that correlates with disease activity states. Gene co-expression domains pertaining to biological functions implicated in SLE such as the interferon pathway, are being disrupted in patients, while others associated to severe manifestations such as nephritis, emerge in previously uncorrelated regions of the genome. Our results support extensive genome re-organization underlying aberrant gene expression in SLE, which could assist in the early detection of disease flares in patients that are in remission. Graphical Abstract3

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Section: Dces Are Dynamically Redistributed In Slementioning

confidence: 62%

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Panousis

Tektonidou

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…2b ). We also employed two different indexes, BP score (BP) [ 52 ] and variation of information (VI) [ 38 ]. Although IS performed best with the two indexes (Additional file 2 : Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Given two sets of domains, T = { T 1 , T 2 , …, T n } and K = { K 1 , K 2 , …, K m }, N is the length of contact matrix. We assess their similarity using adjusted mutual information (AMI) [ 51 ], weighted similarity (WS) [ 42 ], BP distance (BP) [ 52 ], and variation of information (VI) [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell

Zeng

et al. 2021

Genome Biol

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Topologically associating domains (TAD) are a key structure of the 3D mammalian genomes. However, the prevalence and dynamics of TAD-like domains in single cells remain elusive. Here we develop a new algorithm, named deTOKI, to decode TAD-like domains with single-cell Hi-C data. By non-negative matrix factorization, deTOKI seeks regions that insulate the genome into blocks with minimal chance of clustering. deTOKI outperforms competing tools and reliably identifies TAD-like domains in single cells. Finally, we find that TAD-like domains are not only prevalent, but also subject to tight regulation in single cells.

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“…To determine the maximum window size for TAD calls, TAD calls were compared across window sizes for the same patient using the BPscore metric 78 . TAD calls are identical when the BPscore is 0, and divergent when 1.…”

Section: Tad Identificationmentioning

confidence: 99%

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Hawley

Zhou

Arlidge

et al. 2021

Preprint

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Prostate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

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BPscore: An Effective Metric for Meaningful Comparisons of Structural Chromosome Segmentations

Cited by 6 publications

References 29 publications

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

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