Higher-order Genome Organization in Human Disease

Misteli, Tom

doi:10.1101/cshperspect.a000794

Cited by 198 publications

(161 citation statements)

References 104 publications

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“…More probably, specific interphase chromosome organization is rather an element of a pathogenetic pathway rather than a unique underlying disease cause. This idea is further supported by observations on diseases caused by mutations in genes encoding chromatin architecting and remodeling proteins [17] and generation of cancer-causing chromosomal rearrangements [18].…”

Section: Nuclear Genome/chromosome Organization and Diseasesupporting

confidence: 59%

“…Therefore, it is not surprising that a number of diseases associated with genetic defects in genes encoding chromatin architecting and remodeling proteins [17] as well as diseases characterized by genome and/or chromosome instability (i.e. cancers) are hallmarked by alterations to spatial genome organization in interphase nuclei [18].…”

Section: Nuclear Genome/chromosome Organization and Diseasementioning

confidence: 99%

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To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

Iourov¹

2012

Biodiscovery

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The last hierarchical level of cellular genome organization is the spatial arrangement of chromosomes within the nuclear space. Despite of high regulatory potential and functional implications, issues concerning nuclear organization at chromosomal level are rarely addressed because of limitations in visualizing interphase chromosomes. The problem is especially seen when an attempt to associate specific patterns of nuclear genome organization with a pathological condition is made. Fortunately, advances in molecular cytogenetics have provided for a solution to visualize chromosomes in interphase nuclei at molecular resolution. A study in this issue of BioDiscovery shows the way of how to identify interphase chromosome architecture at molecular resolutions and demonstrates the involvement of specific nuclear genome organization in generating a cancercausing chromosomal aberration (translocation between chromosomes 8 and 21 in acute myelogenous leukemia). Authors' findings suggest interphase molecular cytogenetic techniques (i.e. interphase chromosome-specific multicolor banding or ICS-MCB) to be required to perform studies regarding nuclear genome organization at chromosomal level and its role in disease pathogenesis.

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Section: Nuclear Genome/chromosome Organization and Diseasesupporting

confidence: 59%

Section: Nuclear Genome/chromosome Organization and Diseasementioning

confidence: 99%

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

Iourov¹

2012

Biodiscovery

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“…Regardless of whether it will come through the development of new methodologies to probe chromatin organization or through computational/mathematical modeling of population-based datasets, understanding the actual relationship between chromatin architecture and state will be essential to appreciate the natural plasticity of chromatin and identify conformation patterns that lead to improper gene expression and disease. In this respect, chromatin organization is often altered in human diseases such as cancer [102], and we have recently provided evidence of its value as a discovery tool for candidate cancer biomarkers [103]. It will be interesting to see whether chromatin conformations actually represent ideal biomarkers and to define the value of such signatures in the clinic [104].…”

Section: Discussionmentioning

confidence: 99%

Spatial Organization of Epigenomes

2016

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The role of genome architecture in transcription regulation has become the focus of an increasing number of studies over the past decade. Chromatin organization can have a significant impact on gene expression by promoting or restricting the physical proximity between regulatory DNA elements. Given that any change in chromatin state has the potential to alter DNA folding and the proximity between control elements, the spatial organization of chromatin is inherently linked to its molecular composition. In this review, we explore how modulators of chromatin state and organization might keep gene expression in check. We discuss recent findings and present some of the less well-studied aspects of spatial genome organization such as chromatin dynamics and regulation by non-coding RNAs.

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“…One possibility is that these recurrent translocations arise at no more common a frequency than any other translocation but that they are selected on the basis of their potential to drive survival and proliferation of the cancer cell. An additional, long-standing hypothesis is that recurrent translocations arise because the translocation partners are in particularly close proximity to the nuclei of cells from the affected tissue [91][92][93] . Chromosome conformation capture has been used to measure genomic interactions, and combining this technique with deep sequencing has recently enabled the measurement at basepair resolution of how closely genomic loci interact.…”

Section: Factors Favouring Translocationsmentioning

confidence: 99%

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

Nussenzweig¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE: March 20142. REPORT TYPE Annual 3. DATES COVERED (From -To) PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERNational Cancer Institute Bethesda, MD 20892 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical ResearchAnd Materiel Command Fort Detrick, MD 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT :Approved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACTOur proposal is to explore the novel notion that it may be possible to restore near normal HR activity in Brca1 cells and tissues. We believe that this phenomenon will lead to targeted therapies to reduce lifetime risk of tumor formation in BRCA1 and potentially BRCA2 carriers. SUBJECT TERMSBRCA1, 53BP1, cancer biology, DNA repair, tumorigenesis. Appendices……………………………………………………………………………..9 IntroductionGenomic instability is a hallmark of cancer. Central to a cells ability to maintain genomic stability are systems that monitor and repair DNA double strand breaks (DSBs). The objective of this study is to understand how the choice of pathways used to repair DNA damage determines whether the repair is error free or causes genomic instability. In mammalian cells, homologous recombination (HR) and nonhomologous end joining (NHEJ) are the two major pathways involved in the repair of DNA DSBs. The Brca1 gene is required for DNA repair by homologous recombination and normal embryonic development. The protein 53BP1 promotes ligation and facilitates end joining. In previous studies, we have demonstrated that Brca1 and 53BP1 can compete for the processing of DSBs and that 53BP1 can promote genomic instability in the absence of Brca1. Thus, the tumor suppressive function of Brca1 does not appear to be absolute and can be modulated by altering the ability of cells to carryout NHEJ. Our study focuses on shifting the balance between these two repair pathways (HR and NHEJ) to restore error free repair and genomic stability. We believe that a better understanding of mechanisms of DSB repair pathway choice may have ...

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Higher-order Genome Organization in Human Disease

Cited by 198 publications

References 104 publications

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

Spatial Organization of Epigenomes

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

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