Abstract
Spatial expression patterns of homeobox (HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. The molecular mechanism underlying the establishing or maintaining of HOX gene expression pattern remains an attractive developmental issue to be addressed. Our previous work suggested a critical role of CTCF/cohesin-mediated higher- order chromatin structure in RA-induced HOXA activation in human teratocarcinoma NT2/D1 cells. This study investigated the recruitment of CTCF and cohesin, and the higher-order chromatin structure of the HOXA locus in fetal lung and adult foreskin fibroblasts, which display complementary HOXA gene expression patterns. Chromatin contacts between the CTCF-binding sites were observed with lower frequency in human foreskin fibroblasts. This observation is consistent with the lower level of cohesin recruitment and 5' HOXA gene expression in the same cells. We also showed that CTCF-binding site A56 (CBSA56) related chromatin structures exhibit the most notable changes in between the two types of cell, and hence may stand for one of the key CTCF-binding sites for cell-type specific chromatin structure organization. Together, these results imply that CTCF/cohesin coordinates HOXA cluster higher-order chromatin structure and expression during development, and provide insight into the relationship between cell-type specific chromatin organization and the spatial collinearity.
Highlights
Spatial expression patterns of homeobox (HOX) genes delineate positional identity of primary fibroblasts from different topographic sites
To elucidate whether the CCCTC-binding factor (CTCF)/cohesin-mediated chromatin architecture represents a general role in the regulation of HOXA genes, we investigated CTCF and cohesin recruitment, and higher order structure of this locus in the primary fetal lung and foreskin fibroblasts that exhibiting complementary patterns of HOXA gene expression [21]
We showed in this study that CTCF/cohesin bound to the CTCF binding sites (CBSs) in HOXA locus in both human primary lung and foreskin fibroblasts, and that the CBSs are spatially related as have been indicated in the NTERA-2 cl.D1 human teratocarcinoma (NT2/D1) cells
Summary
Spatial expression patterns of homeobox (HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. This study investigated the recruitment of CTCF and cohesin, and the higher-order chromatin structure of the HOXA locus in fetal lung and adult foreskin fibroblasts, which display complementary HOXA gene expression patterns. To elucidate whether the CTCF/cohesin-mediated chromatin architecture represents a general role in the regulation of HOXA genes, we investigated CTCF and cohesin recruitment, and higher order structure of this locus in the primary fetal lung and foreskin fibroblasts that exhibiting complementary patterns of HOXA gene expression [21]. The cell-type-specific enrichment of cohesin coincides with gene expression pattern and 3D organization of HOXA cluster in these cells, implying that CTCF/cohesin participates in regulating HOXA locus expression and spatial structure in primary human cells. We found that CTCF-binding site A56 (CBSA56) likely plays a central role in the spatial organization of HOXA locus, as it gives out the highest and most frequent interactions with other elements in the locus in the 3C assay
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