AI helps you reading Science

AI generates interpretation videos

AI extracts and analyses the key points of the paper to generate videos automatically

Go Generating

AI Traceability

AI parses the academic lineage of this thesis

Generate MRT

AI Insight

AI extracts a summary of this paper

Weibo:

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

Full Text

View via Publisher

Other Links

academic.microsoft.com pubmed.ncbi.nlm.nih.gov

Bibtex

Weibo

Keywords

cr eventgene 1gene 23d structurechromatin interactionMore(17+)

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

Code:

Data:

Insight

Full Text

PPT (Upload PPT)

Similar

Reference

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

Reference

Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010, doi: 10.1038/nature08645 (2009).
Beunders, G. et al. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. American Journal of Human Genetics 92, 210–220, doi: 10.1016/j.ajhg.2012.12.011 (2013).
van Gent, D. C., Hoeijmakers, J. H. & Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nature Reviews Genetics 2, 196–206, doi: 10.1038/35056049 (2001).
Shrivastav, M., De Haro, L. P. & Nickoloff, J. A. Regulation of DNA double-strand break repair pathway choice. Cell Research 18, 134–147, doi: 10.1038/cr.2007.111 (2008).
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Research 44, D862–868, doi: 10.1093/nar/gkv1222 (2016).
Kong, F. et al. dbCRID: a database of chromosomal rearrangements in human diseases. Nucleic Acids Research 39, D895–900, doi: 10.1093/nar/gkq1038 (2011).
Rowley, J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).
Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine 344, 1031–1037, doi: 10.1056/NEJM200104053441401 (2001).
Lanctot, C., Cheutin, T., Cremer, M., Cavalli, G. & Cremer, T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature Reviews Genetics 8, 104–115, doi: 10.1038/nrg2041 (2007).
Nunez, E., Fu, X. D. & Rosenfeld, M. G. Nuclear organization in the 3D space of the nucleus - cause or consequence? Current Opinion in Genetics & Development 19, 424–436, doi: 10.1016/j.gde.2009.07.005 (2009).
Gibcus, J. H. & Dekker, J. The hierarchy of the 3D genome. Molecular Cell 49, 773–782, doi: 10.1016/j.molcel.2013.02.011 (2013).
Sexton, T. & Cavalli, G. The role of chromosome domains in shaping the functional genome. Cell 160, 1049–1059, doi: 10.1016/j. cell.2015.02.040 (2015).
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293, doi: 10.1126/science.1181369 (2009).
Fullwood, M. J. et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462, 58–64, doi: 10.1038/ nature08497 (2009).
Rao, S. S. et al. A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping. Cell 159, 1665–1680, doi: 10.1016/j.cell.2014.11.021 (2014).
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380, doi: 10.1038/nature11082 (2012).
Pope, B. D. et al. Topologically associating domains are stable units of replication-timing regulation. Nature 515, 402–405, doi: 10.1038/nature13986 (2014).
Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025, doi: 10.1016/j.cell.2015.04.004 (2015).
Taberlay, P. C. et al. Three-dimensional disorganisation of the cancer genome occurs coincident with long range genetic and epigenetic alterations. Genome Research, doi: 10.1101/gr.201517.115 (2016).
Sofueva, S. et al. Cohesin-mediated interactions organize chromosomal domain architecture. The EMBO Journal 32, 3119–3129, doi: 10.1038/emboj.2013.237 (2013).
Crane, E. et al. Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523, 240–244, doi: 10.1038/nature14450 (2015).
Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112, doi: 10.1038/nature07829 (2009).
Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F. & Chiang, C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 418, 979–983, doi: 10.1038/nature01033 (2002).
Miller, D. T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics 86, 749–764, doi: 10.1016/j.ajhg.2010.04.006 (2010).
Gao, Z. et al. An AUTS2-Polycomb complex activates gene expression in the CNS. Nature 516, 349–354, doi: 10.1038/nature13921 (2014).
Lesne, A., Riposo, J., Roger, P., Cournac, A. & Mozziconacci, J. 3D genome reconstruction from chromosomal contacts. Nature Methods 11, 1141–1143, doi: 10.1038/nmeth.3104 (2014).
Tang, Z. et al. CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription. Cell 163, 1611–1627, doi: 10.1016/j.cell.2015.11.024 (2015).
Ji, X. et al. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell 18, 262–275, doi: 10.1016/j. stem.2015.11.007 (2016).
Martin, P. et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nature Communications 6, 10069, doi: 10.1038/ncomms10069 (2015).
Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458, doi: 10.1126/ science.aad9024 (2016).
Chen, Y., Wang, Y., Xuan, Z., Chen, M. & Zhang, M. Q. De novo deciphering three-dimensional chromatin interaction and topological domains by wavelet transformation of epigenetic profiles. Nucleic Acids Research 44, e106, doi: 10.1093/nar/gkw225 (2016).
Xu, Z. et al. HiView: an integrative genome browser to leverage Hi-C results for the interpretation of GWAS variants. BMC Research Notes 9, 159, doi: 10.1186/s13104-016-1947-0 (2016).

Author

Ruifeng Li

Yifang Liu

[0]

Tingting Li

Cheng Li (李程)

[0]

Your rating :

No Ratings