Long-range chromosomal interactions and gene regulation

Miele, A.E.; Dekker, Job

doi:10.1039/b803580f

Cited by 188 publications

(139 citation statements)

References 105 publications

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“…3C assays record frequencies at which DNA fragments are in close spatial proximity to one another, and the formation of a 3C product between two DNA fragments is interpreted to demonstrate that those fragments bind factors that interact (15,61,68). While this assay provides a powerful approach to scoring interactions, there are some limitations (39). One limitation that was evident in this study was the paucity of convenient restriction sites that would allow separation of gene promoter regions from CTCF sites.…”

Section: Discussionmentioning

confidence: 88%

CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus

Majumder

Boss

2010

Molecular and Cellular Biology

120

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The major histocompatibility complex class II (MHC-II) locus includes a dense cluster of genes that function to initiate immune responses. Expression of insulator CCCTC binding factor (CTCF) was found to be required for expression of all MHC class II genes associated with antigen presentation. Ten CTCF sites that divide the MHC-II locus into apparent evolutionary domains were identified. To define the role of CTCF in mediating regulation of the MHC II genes, chromatin conformation capture assays, which provide an architectural assessment of a locus, were conducted across the MHC-II region. Depending on whether MHC-II genes and the class II transactivator (CIITA) were being expressed, two CTCF-dependent chromatin architectural states, each with multiple configurations and interactions, were observed. These states included the ability to express MHC-II gene promoter regions to interact with nearby CTCF sites and CTCF sites to interact with each other. Thus, CTCF organizes the MHC-II locus into a novel basal architecture of interacting foci and loop structures that rearranges in the presence of CIITA. Disruption of the rearranged states eradicated expression, suggesting that the formation of these structures is key to coregulation of MHC-II genes and the locus.Spanning nearly 700 kb of the short arm of chromosome 6 at 6p21.31, the major histocompatibility complex class II (MHC-II) locus contains a dense cluster of highly polymorphic genes that encode the alpha and beta chains of the classical MHC-II heterodimeric molecules (reviewed in references 8, 21, and 59). Three MHC-II isotypes, HLA-DR, -DQ, and -DP, can be formed, and they present antigenic peptides to CD4 T lymphocytes in order to initiate, control, and/or maintain adaptive immune responses (20). This antigen presentation process is aided by two MHC-II region-encoded molecules, HLA-DM and HLA-DO, which are also alpha/beta heterodimers with sequence and structural homology with MHC-II proteins (55, 64). The locus includes several MHC-II homologous pseudogenes that represent defunct duplications of ancient MHC-II genes (29). Also within the locus are five genes that do not bear structural homology to MHC-II proteins, the TAP1 and TAP2 genes involved in peptide transport for MHC-I antigen presentation, the proteasome 20s core beta subunit genes PSMB8 and PSMB9, and the bromodomain and extra terminal domain transcriptional regulator gene BRD2 (25,38,67).MHC-II genes are expressed in B lymphocytes, macrophages, and dendritic cells and certain cells within the thymus. Gamma interferon (IFN-␥) is a potent inducer of MHC-II gene expression in most cell types (12). The transcription factors RFX (regulatory factor X), CREB (cyclic AMP [cAMP] response element binding protein), and NF-Y (nuclear factor Y) are constitutively and ubiquitously expressed and bind to highly conserved MHC-II gene-and related gene promoterproximal sequences termed the X1, X2, and Y boxes (9, 51, 59). CIITA (class II transactivator) interacts with the X-Y box-bound factors and mediates the i...

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Section: Discussionmentioning

confidence: 88%

CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus

Majumder

Boss

2010

Molecular and Cellular Biology

120

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“…Second, evolutionary studies identify well-conserved segments within distal noncoding regions, implying functional significance. Finally, there is growing evidence for distal regulatory interactions mediated by chromatin loops throughout the genome, perhaps best studied in mammals at the globin locus with the distal locus control region that regulates sequential gene expression during development (Tolhuis et al 2002;Miele and Dekker 2008).…”

Section: Mechanism Of Distal Regulationmentioning

confidence: 99%

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Cole

2014

Cold Spring Harbor Perspectives in Medicine

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MYC is one of the most frequently mutated and overexpressed genes in human cancer but the regulation of MYC expression and the ability of MYC protein to repress cellular genes (including itself ) have remained mysterious. Recent genome-wide association studies show that many genetic polymorphisms associated with disease risk map to distal regulatory elements that regulate the MYC promoter through large chromatin loops. Cancer risk-associated single-nucleotide polymorphisms (SNPs) contain more potent enhancer activity, promoting higher MYC levels and a greater risk of disease. The MYC promoter is also subject to complex regulatory circuits and limits its own expression by a feedback loop. A model for MYC autoregulation is discussed which involves a signaling pathway between the PTEN ( phosphatase and tensin homolog) tumor suppressor and repressive histone modifications laid down by the EZH2 methyltransferase.

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“…3C-based studies have convincingly shown that regulatory elements can act over large genomic distances by chromatin looping (Cai et al, 2006;Fullwood et al, 2009;Kurukuti et al, 2006;Majumder et al, 2008;Spilianakis and Flavell, 2004;Tiwari et al, 2008b;Tolhuis et al, 2002;Vakoc et al, 2005;Vernimmen et al, 2007;Zhou et al, 2006). The role of long-range looping interactions in gene regulation has been extensively covered in a number of recent reviews (Chambeyron and Bickmore, 2004;de Laat and Grosveld, 2003;Dekker, 2008;Fraser, 2006;Göndör and Ohlsson, 2009;Kadauke and Blobel, 2009;Miele and Dekker, 2008;Vilar and Saiz, 2005), and will not be treated here in detail. We speculate that the formation of the large spatial compartments that are enriched in active chromatin segments described above brings large sets of genes and regulatory elements located in different domains along the linear genome in general spatial proximity (mainly in cis, but also in trans).…”

Section: Spatial Compartmentalization Of the Genomementioning

confidence: 99%

“…Chromosomes are not simply 1D entities -their 3D organization inside the nucleus can have important roles in genome regulation (Dekker, 2008;Fraser and Bickmore, 2007;Miele and Dekker, 2008;Misteli, 2007). The 3D organization of chromosomes -and the nucleus in general -has traditionally been studied by microscopic methods.…”

Section: Spatial Compartmentalization Of the Genomementioning

confidence: 99%

“…Similar results were obtained in studies of the transcription factor GATA1 (Cheng et al, 2009;Fujiwara et al, 2009;Yu et al, 2009): this erythroid-specific transcriptional regulator binds sites that, in almost 50% of cases, are located further than 10 Kb from the nearest putative target gene. These studies imply that long-range phenomena, in which regulatory elements must act over large genomic distances (up to hundreds of Kb or more) to regulate genes, must be quite prevalent (Miele and Dekker, 2008).…”

Section: Genes and Their Regulatory Elements Can Be Far Apart And Outmentioning

confidence: 99%

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Integrating one-dimensional and three-dimensional maps of genomes

Naumova

Dekker

2010

Journal of Cell Science

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SummaryGenomes exist in vivo as complex physical structures, and their functional output (i.e. the gene expression profile of a cell) is related to their spatial organization inside the nucleus as well as to local chromatin status. Chromatin modifications and chromosome conformation are distinct in different tissues and cell types, which corresponds closely with the diversity in gene-expression patterns found in different tissues of the body. The biological processes and mechanisms driving these general correlations are currently the topic of intense study. An emerging theme is that genome compartmentalization -both along the linear length of chromosomes, and in three dimensions by the spatial colocalization of chromatin domains and genomic loci from across the genome -is a crucial parameter in regulating genome expression. In this Commentary, we propose that a full understanding of genome regulation requires integrating three different types of data: first, one-dimensional data regarding the state of local chromatin -such as patterns of protein binding along chromosomes; second, three-dimensional data that describe the population-averaged folding of chromatin inside cells and; third, single-cell observations of three-dimensional spatial colocalization of genetic loci and trans factors that reveal information about their dynamics and frequency of colocalization.This article is part of a Minifocus on exploring the nucleus. For further reading, please see related articles: 'The nuclear envelope at a glance' by Katherine L. Wilson and Jason M. Berk (J. Cell Sci. 123, 1973-1978 and 'Connecting the transcription site to the nuclear pore: a multi-tether process regulating gene expression' by Guennaëlle Dieppois and Françoise Stutz (J. Cell Sci. 123, 1989.

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Long-range chromosomal interactions and gene regulation

Cited by 188 publications

References 105 publications

CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus

CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Integrating one-dimensional and three-dimensional maps of genomes

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