Human Epigenomics by Carsten Carlberg & Ferdinand Molnár

Author:Carsten Carlberg & Ferdinand Molnár
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

Regulatory loops are formed between enhancers and TSS regions that are located within the same TAD, i.e. they are smaller than TADs (Fig. 7.5). In fact, the maximal linear size distance between an enhancer and the TSS of a gene that it is regulating is determined by the size of the TAD within they reside. The formation of regulatory loops relies on the binding of transcription factors to the enhancer regions and in a few cases depends also on CTCF and cohesin. The functional result of regulatory loop formation is the stimulation of gene expression. Interestingly, there are also regulatory loops between the beginning and the end of a gene. For example, the promoter regions of rRNA genes form loops with terminator sequences of the same gene. These loops are associated with increased rRNA expression, because they facilitate reloading of RNA polymerase I to the TSS. This promoter-terminator looping applies also for some Pol II genes. Such gene loops represent a kind of transcriptional memory, where a loop formed after an initial round of gene activation speeds up the reactivation of the gene.

TADs subdivide chromosomes into structural domains and also serve as functional units (Fig. 7.5). Due to the high evolutionary conservation of CTCF binding sites many TADs are tissue-invariant and even conserved between species. Nevertheless, 30–50% of the TADs still differ between cell types. Neighboring TADs can differ significantly in their histone modification pattern, such as one TAD being in heterochromatic state containing silent genes and the other TAD being in euchromatin carrying transcriptionally active genes. Thus, TAD boundaries often separate chromatin regions of different activity from each other, i.e. they act as insulators (Sect. 4.​4). Most TAD boundaries contain CTCF-binding motifs in a convergent (forward-reverse) orientation, which is crucial for loop formation via a pair of CTCF molecules that are kept together by cohesin rings.

GWAS led to the identification of a large number of disease-associated loci, the vast majority of which are located in regulatory but not in coding regions of genes. This means that the physiological consequences of most variations, mutations and rearrangements of the human genome rather have an epigenomic or gene regulatory basis than affecting proteins encoded by respective genes. For example, the disruption of CTCF binding sites by deletions or inversions can destroy TAD boundaries and may have consequences on the regulation of genes within the neighboring TADs. In a hypothetical example gene 1 is silenced within the repressive TAD 1, while gene 2 is activated by an enhancer within the neighboring TAD 2 (Fig. 7.6a). This wild type gene regulatory scenario can be disturbed by deletion of the boundary region between the two TADs resulting in activation of gene 1 (Fig. 7.6b). Similarly, gene 1 may be activated by inversion (Fig. 7.6c) or duplication (Fig. 7.6d) of the genomic region of the TAD boundary.

Fig. 7.6Disturbing TAD structures by genomic mutations or chromosomal rearrangements. In the wild type case TAD 1 (purple) is separated by a boundary region (“Brick wall”) from TAD 2 (beige)

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.