enclosen, "to surround (a plot of ground, a town, a building, etc.) with walls, fences, or other barriers," early 14c., from en- (1) + close (v.), and partially from Old French enclos, past participle of enclore "surround; confine; contain." Specific sense of "to fence in waste or common ground" for the purpose of cultivation or to give it to private owners is from c. 1500. Meaning "place a document with a letter for transmission" is from 1707. Related: Enclosed; enclosing.
Also used with native and imported elements to form verbs from nouns and adjectives, with a sense "put in or on" (encircle), also "cause to be, make into" (endear), and used as an intensive (enclose). Spelling variants in French that were brought over into Middle English account for parallels such as ensure/insure, and most en- words in English had at one time or another a variant in in-, and vice versa.
enclose
(klōz), c. 1200, "to shut, cover in," from Old French clos- (past participle stem of clore "to shut, to cut off from"), 12c., from Latin clausus, past participle of claudere "to shut, close; to block up, make inaccessible; put an end to; shut in, enclose, confine" (always -clusus, -cludere in compounds), from PIE root *klau- "hook," also "peg, nail, pin," all things used as locks or bolts in primitive structures.
Objectives: This study sought to evaluate the safety and the acute and 1 year outcomes of an ablation protocol aiming to enclose the PV with a contiguous and optimized RF circle by targeting region-specific criteria for lesion depth assessed by ablation index and interlesion distance.
Where notation is a comma-separated list of MathML notations (e.g., circle, left,updiagonalstrike, longdiv, etc.), attributes areMathML attribute values allowed on the element(e.g., mathcolor="red", mathbackground="yellow"), andmath is the mathematics to be enclosed. See the MathML 3specificationfor more details on .
This extension is loaded automatically when the autoload extensionis used. To load the enclose extension explicitly, add'[tex]/enclose' to the load array of the loader block ofyour MathJax configuration, and add 'enclose' to the packagesarray of the tex block.
We use CTCF ChIA-PET data from the ENCODE project to show that CTCF-associated chromatin loops have a tendency to enclose regions of enhancer-regulated stimulus responsive genes, insulating them from neighboring regions of constitutively expressed housekeeping genes. To facilitate cell type-specific CTCF loop identification, we develop an algorithm to predict CTCF loops from ChIP-seq data alone by exploiting the CTCF motif directionality in loop anchors. We apply this algorithm to a hundred ENCODE cell line datasets, confirming the universality of our observations as well as identifying a general distinction between primary and immortal cells in loop-enclosed gene content. Finally, we combine the existing evidence to propose a model for the formation of CTCF loops in which partner sites are brought together by chromatin template reeling through stationary RNA polymerases, consistent with the transcription factory hypothesis.
Here we investigate this hypothesis computationally, seeking to identify whether there is a genome-wide tendency for CTCF loops to enclose stimulus responsive enhancer-regulated genes. We used CTCF ChIA-PET data from human K562 and MCF-7 cells provided by the ENCODE project [25], which are more comprehensive than the mouse CTCF ChIA-PET data analyzed in the previous study. We additionally predicted CTCF loops from genome-wide CTCF binding site data for a hundred cell line datasets provided by the ENCODE project, using an algorithm we developed that exploits the motif directionality in CTCF loop anchors [26, 27]. We find a general tendency for CTCF loops to enclose stimulus responsive genes that are associated with enhancer-based regulation. We also find global differences in loop-enclosed genes between primary and immortal cells, with the former containing more predicted CTCF loop-enclosed genes that are enriched for transcription regulation, cell motility regulation and stem cell differentiation. Finally, we discuss the implications of the motif directionality in CTCF loop anchors, which point to a model of CTCF loop formation involving the reeling of the chromatin template through stationary RNA polymerases, consistent with the transcription factory model of transcription [28].
Genomic properties of CTCF loops and flanking regions. a Profiles of H3K4me1 histone mark and gene and exon density across genomic regions within and around CTCF ChIA-PET loops in both MCF-7 and K562 cells. The loops and their flanking regions are split into bins each spanning 10 % of the loop length. For each bin, the median feature coverage for all loops is plotted. Profiles were normalized by subtracting the mean of all bins, displaying only the variation pattern across the profile. This was done because mean genomic bin coverage can vary substantially between chromatin marks and other genomic features, separating the profiles along the Y-axis and making pattern comparison more difficult. b Profiles of enhancer- and transcription-related chromatin states as defined by the ChromHMM algorithm, within and around CTCF ChIA-PET loops in K562 cells. Processed as above, but without normalizing the means as all the profiles have similar means. Weak transcription differs from the normal transcription state in that it is associated with transcript production but not with any further chromatin marks. c Expression level distribution for genes within and flanking CTCF ChIA-PET loops in K562 and MCF-7 cells. Flanking regions are equal in size to the loops they flank. Flanking genes located within neighboring loops are excluded from the set of flanking genes; there is no overlap between loop-enclosed and loop-flanking genes. Expression data are from the same cell lines as the corresponding loop sets. d Tissue Specificity Index (TSI, see methods) distribution for genes within and flanking CTCF ChIA-PET loops. Flanking genes are chosen as described above. e Coefficient of Variation (CV) distribution for genes within and flanking CTCF ChIA-PET loops. CV (standard deviation/mean) indicates the degree of variability in expression level of a gene across tissues. Flanking genes are chosen as described above
We applied our CTCF loop prediction algorithm to 100 CTCF ChIP-seq datasets generated by the ENCODE consortium [25], in order to investigate the generality of the enrichment of stimulus response genes within CTCF-enclosed chromatin domains (Additional file 3: Table S2 and ). Due to the variability in ChIP-seq datasets and correspondingly in loop prediction between different labs even for the same cell line (Additional file 1: Figure 2B), we restricted our analysis to the 50 cell line datasets generated by the University of Washington (UW) [25]. Using K-means clustering, we clustered the genes into six clusters based on their pattern of loop membership across cell lines (Fig. 3a). Similar results are obtained with different choices of cluster number (Additional file 1: Figure S3). While the largest cluster (cluster 1; 13681 genes) contains genes absent from strong predicted CTCF loops in virtually all cell lines, the next largest (cluster 3; 3293 genes) contains genes predicted to lie within strong CTCF loops in the majority of cell lines. Consistent with the genes located within ChIA-PET loops in K562 and MCF-7 cells, this latter cluster is enriched for genes involved in the regulation of cellular responses to external signals (Additional file 4: Table S3).
Gene content similarities and differences between ENCODE cell lines for predicted CTCF loops. a Heatmap showing similarity of predicted CTCF loop-enclosed gene content across the University of Washington ENCODE cell lines. Genes are clustered into six clusters using K-means clustering. Cell lines are clustered hierarchically based on the K-means cluster patterns, using the average linkage algorithm and Euclidean distances. Heatmap colors indicate the proportion of genes from that cluster falling within CTCF loops in that cell line. b Predicted CTCF loop gene count distributions for primary and immortal cells, for all ENCODE datasets and for the subset from the University of Washington (UW). Notches extend 1.58*IQR/sqrt(n) from the medians and roughly correspond to their 95% confidence intervals (IQR = inter-quartile range). c CTCF ChIP-seq peak count distributions for primary and immortal cells (all ENCODE datasets and UW-only datasets). d Principal Components Analysis (PCA) of cell lines based on their predicted CTCF loop-enclosed gene content (PC1 vs PC2 plotted)
A common theme to the functions associated with gene clusters enriched for CTCF loop-enclosed genes in multiple cell types (clusters 2,3,4 & 6) is the preponderance of regulatory processes. In contrast, genes that are rarely or never located within putative CTCF loops (clusters 1 & 4) are enriched for housekeeping processes and for genes that are involved in specialized and highly cell type-specific biological processes, such as olfactory receptors (Additional file 4: Table S3). This is consistent with the observation that genes with complex regulatory requirements have intermediate levels of tissue-specificity in their expression patterns [32], and with CTCF playing a role in the genomic organization of genes requiring dynamic regulation and rapid changes in expression levels.
A major role of CTCF-mediated chromatin loops, particularly those that are less than 200kb long, appears to be to enclose enhancer-regulated gene domains, particularly those involved in responding to stimuli. This looping may facilitate rapid changes in transcription rate by stabilizing pre-formed enhancer-promoter chromatin hubs that can readily be converted into, or recruited to, active transcription factories. It may also permit such genes to be controlled independently from neighboring constitutively expressed housekeeping genes. CTCF-mediated chromatin loops can be predicted from ChIP-seq data due to the CTCF binding orientation preference at interacting loop anchors. This orientation preference suggests that these loops may be formed by relatively stationary RNAPII molecules reeling in the chromatin template, thereby bringing together distant CTCF genomic binding sites into close spatial proximity in the nucleus. 2ff7e9595c
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