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Follow-up validations may compare the gene expression level of normal people and patients with Chromosomal rearrangement in affected cell types, and use 4C and CRISPR experiments to inspect the impact of CRs on chromatin interactions

3disease Browser: A Web Server For Integrating 3d Genome And Disease-Associated Chromosome Rearrangement Data

SCIENTIFIC REPORTS, (2016): 34651

Cited: 26|Views10
WOS NATURE

Abstract

Chromosomal rearrangement (CR) events have been implicated in many tumor and non-tumor human diseases. CR events lead to their associated diseases by disrupting gene and protein structures. Also, they can lead to diseases through changes in chromosomal 3D structure and gene expression. In this study, we search for CR-associated diseases p...More

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Introduction
  • Advances in DNA microarray and sequencing technologies have led to accurate identification of CR events and chromosomal 3D structures in large scale[5,13].
  • The authors predicted disease-associated CR events that may alter chromosomal 3D structure by integrating Hi-C and ChIP-seq data sets.
  • The authors developed a Web server for exploring the relationship between disease-associated CR events and chromosome 3D structures of multiple human cell types
Highlights
  • In recent years, advances in DNA microarray and sequencing technologies have led to accurate identification of Chromosomal rearrangement (CR) events and chromosomal 3D structures in large scale[5,13]
  • CR events are frequently associated with cancer and developmental diseases
  • In addition to their roles in disrupting coding regions, recent studies found that CRs may alter gene expression by affecting chromosomal structures
  • We developed a method to predict disease-associated CRs that may influence chromosomal 3D structure using Hi-C and ChIP-seq data
  • Among our top predicted CR events, intellectual disability is a candidate disease caused by TAD-affecting CRs
  • Follow-up validations may compare the gene expression level of normal people and patients with CR in affected cell types, and use 4C and CRISPR experiments to inspect the impact of CRs on chromatin interactions
Methods
  • GM12878 is a lymphoblastoid cell line produced from the blood of a female with European ancestry.
  • HESC is an embryonic stem cell line from a normal male.
  • HMEC is a mammary epithelial cell line from a normal person.
  • HUVEC is an umbilical vein endothelial cell line from a normal person.
  • NHEK is an epidermal keratinocyte cell line from the skin of a normal person.
  • The ChIP-seq data of the above cell lines come from the ENCODE project.
  • The CR data come from ClinVar (Release 2015-12, http://www.ncbi.nlm.nih.gov/clinvar/) and manual search of PubMed
Results
  • Predicting disease-associated CR events that affect TADs.

    Based on previous studies, abnormal 3D chromosome structure may be a consequence of CR events leading to diseases.
  • When CR events affect TAD boundaries, they alter the interactions between genes and enhancers, leading to abnormal expression of genes (Fig. 1a).
  • The enhancer is moved out of TAD B and placed near gene 2 (G2), and the boundary is on the right side of E
  • This results in interaction between E and G2, but prevents the original interaction between E and G1.
  • If a deletion event removes the boundary B1 and parts of TAD A and TAD B, the two TADs merge and E is able to interact with both G1 and G2, resulting in abnormal expression of G2
Conclusion
  • CR events are frequently associated with cancer and developmental diseases.
  • In addition to their roles in disrupting coding regions, recent studies found that CRs may alter gene expression by affecting chromosomal structures.
  • The authors developed a method to predict disease-associated CRs that may influence chromosomal 3D structure using Hi-C and ChIP-seq data.
  • The authors' method rediscovers experimentally validated disease-causing CRs in the polydactyly diseases that alter gene expression by disrupting chromosome 3D structure[18].
  • Follow-up validations may compare the gene expression level of normal people and patients with CR in affected cell types, and use 4C and CRISPR experiments to inspect the impact of CRs on chromatin interactions
Tables
  • Table1: Top 20 diseases whose associated CRs are predicted to affect TAD. CR ID: ID in 3Disease Browser. Gene is the candidate gene name affected by CR events. SI Score (hESC) is calculated using hESC cell line’s data
  • Table2: Five CRs associated with limb developmental disorders. CR ID: ID in 3Disease Browser. SI Score (hESC) is calculated using hESC cell line’s data
  • Table3: Comparison of 3D genome browsers
Download tables as Excel
Funding
  • The work is supported by grants from Peking-Tsinghua Center for Life Sciences. Author Contributions R.L., T.L. and C.L. designed the study
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Author
Ruifeng Li
Ruifeng Li
Tingting Li
Tingting Li
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