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A discrete transition zone organizes the topological and regulatory autonomy of the adjacent tfap2c and bmp7 genes.

Tsujimura T, Klein FA, Langenfeld K, Glaser J, Huber W, Spitz F - PLoS Genet. (2015)

Bottom Line: The impact of engineered chromosomal rearrangements on the topology of the locus and the resultant gene expression changes indicate that this transition zone functionally organizes the structural partition of the locus, thereby defining enhancer-target gene allocation.This partition is, however, not absolute: we show that it allows competing interactions across it that may be non-productive for the competing gene, but modulate expression of the competed one.Altogether, these data highlight the prime role of the topological organization of the genome in long-distance regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.

ABSTRACT
Despite the well-documented role of remote enhancers in controlling developmental gene expression, the mechanisms that allocate enhancers to genes are poorly characterized. Here, we investigate the cis-regulatory organization of the locus containing the Tfap2c and Bmp7 genes in vivo, using a series of engineered chromosomal rearrangements. While these genes lie adjacent to one another, we demonstrate that they are independently regulated by distinct sets of enhancers, which in turn define non-overlapping regulatory domains. Chromosome conformation capture experiments reveal a corresponding partition of the locus in two distinct structural entities, demarcated by a discrete transition zone. The impact of engineered chromosomal rearrangements on the topology of the locus and the resultant gene expression changes indicate that this transition zone functionally organizes the structural partition of the locus, thereby defining enhancer-target gene allocation. This partition is, however, not absolute: we show that it allows competing interactions across it that may be non-productive for the competing gene, but modulate expression of the competed one. Altogether, these data highlight the prime role of the topological organization of the genome in long-distance regulation of gene expression.

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Redistribution of the interaction domains upon chromosomal inversions.4C profiles were compared amongst WT control (A), INV-M (B) and INV-L2 (C) alleles for the four viewpoints indicated with black triangles. For inversion plots, the genomic coordinates were reordered to take the genomic rearrangements into account: hence, representated profiles correspond to the actual genomic structure of each allele. Representations of the data aligned on the reference (WT) genome are available in S8 and S9 Figs. Dashed rectangles and light-blue bars represent the regions inverted in the INV-M and INV-L2 alleles. The position of the TZ is marked by pink columns. The heart (mm75) and forebrain (FB1) enhancers are depicted as pink and blue ovals, respectively. The bars below each plot represent the corresponding primary interaction domain.
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pgen-1004897-g005: Redistribution of the interaction domains upon chromosomal inversions.4C profiles were compared amongst WT control (A), INV-M (B) and INV-L2 (C) alleles for the four viewpoints indicated with black triangles. For inversion plots, the genomic coordinates were reordered to take the genomic rearrangements into account: hence, representated profiles correspond to the actual genomic structure of each allele. Representations of the data aligned on the reference (WT) genome are available in S8 and S9 Figs. Dashed rectangles and light-blue bars represent the regions inverted in the INV-M and INV-L2 alleles. The position of the TZ is marked by pink columns. The heart (mm75) and forebrain (FB1) enhancers are depicted as pink and blue ovals, respectively. The bars below each plot represent the corresponding primary interaction domain.

Mentions: To examine at the consequences of these rearrangements on the structural conformation of the region, we performed 4C experiments on INV-M and INV-L2 embryos (Fig. 5, S8–S10 Figs.). In INV-M, as in WT controls, Tfap2c showed robust interactions over a domain extending up to the TZ. Due to the inversion, this domain now included the heart enhancer, which displayed much stronger interaction with Tfap2c than those observed in WT (S8A Fig., pink versus grey arrow), a result consistent with mm75 now activating Tfap2c. Conversely, the new primary interaction domain of Bmp7 stopped at the TZ, with a very reduced 4C signal over the heart enhancer in INV-M when compared to WT (S8D Fig., grey versus pink arrow). The viewpoint located between mm75 and TZ, which was part of the Bmp7 interaction domain in WT, showed in INV-M broad and extended contacts overlapping with the Tfap2c interaction domain, ending at the TZ region (Fig. 5B). Interestingly, the inversion had no effect on the 4C profile of the TZ-associated viewpoint, which extended on both sides in all configurations. Thus, in INV-M as in WT, the locus appeared structurally partitioned at the TZ: instead of maintaining their normal contacts and regulatory preferences, genes and regulatory elements established new interactions, depending on their respective position in relation to the TZ.


A discrete transition zone organizes the topological and regulatory autonomy of the adjacent tfap2c and bmp7 genes.

Tsujimura T, Klein FA, Langenfeld K, Glaser J, Huber W, Spitz F - PLoS Genet. (2015)

Redistribution of the interaction domains upon chromosomal inversions.4C profiles were compared amongst WT control (A), INV-M (B) and INV-L2 (C) alleles for the four viewpoints indicated with black triangles. For inversion plots, the genomic coordinates were reordered to take the genomic rearrangements into account: hence, representated profiles correspond to the actual genomic structure of each allele. Representations of the data aligned on the reference (WT) genome are available in S8 and S9 Figs. Dashed rectangles and light-blue bars represent the regions inverted in the INV-M and INV-L2 alleles. The position of the TZ is marked by pink columns. The heart (mm75) and forebrain (FB1) enhancers are depicted as pink and blue ovals, respectively. The bars below each plot represent the corresponding primary interaction domain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288730&req=5

pgen-1004897-g005: Redistribution of the interaction domains upon chromosomal inversions.4C profiles were compared amongst WT control (A), INV-M (B) and INV-L2 (C) alleles for the four viewpoints indicated with black triangles. For inversion plots, the genomic coordinates were reordered to take the genomic rearrangements into account: hence, representated profiles correspond to the actual genomic structure of each allele. Representations of the data aligned on the reference (WT) genome are available in S8 and S9 Figs. Dashed rectangles and light-blue bars represent the regions inverted in the INV-M and INV-L2 alleles. The position of the TZ is marked by pink columns. The heart (mm75) and forebrain (FB1) enhancers are depicted as pink and blue ovals, respectively. The bars below each plot represent the corresponding primary interaction domain.
Mentions: To examine at the consequences of these rearrangements on the structural conformation of the region, we performed 4C experiments on INV-M and INV-L2 embryos (Fig. 5, S8–S10 Figs.). In INV-M, as in WT controls, Tfap2c showed robust interactions over a domain extending up to the TZ. Due to the inversion, this domain now included the heart enhancer, which displayed much stronger interaction with Tfap2c than those observed in WT (S8A Fig., pink versus grey arrow), a result consistent with mm75 now activating Tfap2c. Conversely, the new primary interaction domain of Bmp7 stopped at the TZ, with a very reduced 4C signal over the heart enhancer in INV-M when compared to WT (S8D Fig., grey versus pink arrow). The viewpoint located between mm75 and TZ, which was part of the Bmp7 interaction domain in WT, showed in INV-M broad and extended contacts overlapping with the Tfap2c interaction domain, ending at the TZ region (Fig. 5B). Interestingly, the inversion had no effect on the 4C profile of the TZ-associated viewpoint, which extended on both sides in all configurations. Thus, in INV-M as in WT, the locus appeared structurally partitioned at the TZ: instead of maintaining their normal contacts and regulatory preferences, genes and regulatory elements established new interactions, depending on their respective position in relation to the TZ.

Bottom Line: The impact of engineered chromosomal rearrangements on the topology of the locus and the resultant gene expression changes indicate that this transition zone functionally organizes the structural partition of the locus, thereby defining enhancer-target gene allocation.This partition is, however, not absolute: we show that it allows competing interactions across it that may be non-productive for the competing gene, but modulate expression of the competed one.Altogether, these data highlight the prime role of the topological organization of the genome in long-distance regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.

ABSTRACT
Despite the well-documented role of remote enhancers in controlling developmental gene expression, the mechanisms that allocate enhancers to genes are poorly characterized. Here, we investigate the cis-regulatory organization of the locus containing the Tfap2c and Bmp7 genes in vivo, using a series of engineered chromosomal rearrangements. While these genes lie adjacent to one another, we demonstrate that they are independently regulated by distinct sets of enhancers, which in turn define non-overlapping regulatory domains. Chromosome conformation capture experiments reveal a corresponding partition of the locus in two distinct structural entities, demarcated by a discrete transition zone. The impact of engineered chromosomal rearrangements on the topology of the locus and the resultant gene expression changes indicate that this transition zone functionally organizes the structural partition of the locus, thereby defining enhancer-target gene allocation. This partition is, however, not absolute: we show that it allows competing interactions across it that may be non-productive for the competing gene, but modulate expression of the competed one. Altogether, these data highlight the prime role of the topological organization of the genome in long-distance regulation of gene expression.

Show MeSH
Related in: MedlinePlus