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Getting the genome in shape: the formation of loops, domains and compartments.

Bouwman BA, de Laat W - Genome Biol. (2015)

Bottom Line: The hierarchical levels of genome architecture exert transcriptional control by tuning the accessibility and proximity of genes and regulatory elements.Here, we review current insights into the trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute - KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.

ABSTRACT
The hierarchical levels of genome architecture exert transcriptional control by tuning the accessibility and proximity of genes and regulatory elements. Here, we review current insights into the trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.

No MeSH data available.


Convergent CTCF sites at topologically associated domain (TAD) boundaries. The linear distribution of CTCF binding sites and regulatory elements across a hypothetical chromosomal segment (top) results in three-dimensional looped configurations (bottom) that will differ between cells and change over time. CTCF-mediated loops can create TADs, within which enhancer-promoter loops are formed. Loops preferentially occur between convergent CTCF sites, which predicts that a TAD boundary needs to have divergent CTCF sites to accommodate looping with its neighboring boundaries. Note that not all CTCF sites form loops, even when associated with CTCF
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Fig2: Convergent CTCF sites at topologically associated domain (TAD) boundaries. The linear distribution of CTCF binding sites and regulatory elements across a hypothetical chromosomal segment (top) results in three-dimensional looped configurations (bottom) that will differ between cells and change over time. CTCF-mediated loops can create TADs, within which enhancer-promoter loops are formed. Loops preferentially occur between convergent CTCF sites, which predicts that a TAD boundary needs to have divergent CTCF sites to accommodate looping with its neighboring boundaries. Note that not all CTCF sites form loops, even when associated with CTCF

Mentions: The loops formed between TAD boundaries seem to exemplify the longest-range contacts that are stably and reproducibly formed between specific pairs of sequences. Although the mechanisms that underlie the looping of TAD boundaries are largely unknown, numerous reports have identified transcriptional repressor CTCF and the cohesin complex at the sites that anchor these loops [16, 18, 62]. This is in line with previous studies that characterized CTCF at sites separating active and repressed chromatin [39, 63, 64], and that identified both CTCF and cohesin at sites anchoring long-range chromatin contacts [30, 65–68]. CTCF can form dimers in vitro and in vivo [69], and two CTCF molecules bound to distal genomic sites might therefore have the autonomous capacity to form chromatin loops. CTCF has a relatively long non-palindromic DNA recognition sequence [18, 70], and a recent genome-wide assessment of CTCF-bound chromatin loops revealed a strong preference for loops formed between convergently oriented CTCF binding sites (Fig. 2) [18]. The lower efficiency of chromatin looping between CTCF molecules of different orientations could suggest that there is not much intramolecular structural flexibility to accommodate stable long-range interactions, either in the CTCF protein itself or in the chromatin template. Furthermore, if CTCF binding polarity is indeed important for looping, one might expect to find divergent CTCF sites at TAD boundaries because they otherwise cannot capture their two flanking domains in independent loops. In agreement with this, a recent study suggested that diverging CTCF sites represent a general signature of TAD borders in mammals as well as in deuterostomes [71].Fig. 2


Getting the genome in shape: the formation of loops, domains and compartments.

Bouwman BA, de Laat W - Genome Biol. (2015)

Convergent CTCF sites at topologically associated domain (TAD) boundaries. The linear distribution of CTCF binding sites and regulatory elements across a hypothetical chromosomal segment (top) results in three-dimensional looped configurations (bottom) that will differ between cells and change over time. CTCF-mediated loops can create TADs, within which enhancer-promoter loops are formed. Loops preferentially occur between convergent CTCF sites, which predicts that a TAD boundary needs to have divergent CTCF sites to accommodate looping with its neighboring boundaries. Note that not all CTCF sites form loops, even when associated with CTCF
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Convergent CTCF sites at topologically associated domain (TAD) boundaries. The linear distribution of CTCF binding sites and regulatory elements across a hypothetical chromosomal segment (top) results in three-dimensional looped configurations (bottom) that will differ between cells and change over time. CTCF-mediated loops can create TADs, within which enhancer-promoter loops are formed. Loops preferentially occur between convergent CTCF sites, which predicts that a TAD boundary needs to have divergent CTCF sites to accommodate looping with its neighboring boundaries. Note that not all CTCF sites form loops, even when associated with CTCF
Mentions: The loops formed between TAD boundaries seem to exemplify the longest-range contacts that are stably and reproducibly formed between specific pairs of sequences. Although the mechanisms that underlie the looping of TAD boundaries are largely unknown, numerous reports have identified transcriptional repressor CTCF and the cohesin complex at the sites that anchor these loops [16, 18, 62]. This is in line with previous studies that characterized CTCF at sites separating active and repressed chromatin [39, 63, 64], and that identified both CTCF and cohesin at sites anchoring long-range chromatin contacts [30, 65–68]. CTCF can form dimers in vitro and in vivo [69], and two CTCF molecules bound to distal genomic sites might therefore have the autonomous capacity to form chromatin loops. CTCF has a relatively long non-palindromic DNA recognition sequence [18, 70], and a recent genome-wide assessment of CTCF-bound chromatin loops revealed a strong preference for loops formed between convergently oriented CTCF binding sites (Fig. 2) [18]. The lower efficiency of chromatin looping between CTCF molecules of different orientations could suggest that there is not much intramolecular structural flexibility to accommodate stable long-range interactions, either in the CTCF protein itself or in the chromatin template. Furthermore, if CTCF binding polarity is indeed important for looping, one might expect to find divergent CTCF sites at TAD boundaries because they otherwise cannot capture their two flanking domains in independent loops. In agreement with this, a recent study suggested that diverging CTCF sites represent a general signature of TAD borders in mammals as well as in deuterostomes [71].Fig. 2

Bottom Line: The hierarchical levels of genome architecture exert transcriptional control by tuning the accessibility and proximity of genes and regulatory elements.Here, we review current insights into the trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute - KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.

ABSTRACT
The hierarchical levels of genome architecture exert transcriptional control by tuning the accessibility and proximity of genes and regulatory elements. Here, we review current insights into the trans-acting factors that enable the genome to flexibly adopt different functionally relevant conformations.

No MeSH data available.