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Pseudogenes contribute to the evolution of topological domains across species via forming three-dimensional genome [hESC_KO_Hi-C]

ABSTRACT: The human genome harbors 15,000 pseudogenes, except very few can transcribe non-coding RNAs or encode truncated proteins, a large number of which without transcriptional capacity are functionally unknown. Here, we proposed and verified that pseudogene DNA sequences can form chromatin contacts that act as anchors of chromatin loops and boundaries of topologically associating domains (TADs). More amazing, due to the sequence-specificity of pseudogenes, TAD boundaries containing them in the human genome were primarily species-specific, including human-specific and primate-specific ones. We found that during primate evolution, by inheritance from parent genes, certain pseudogenes can introduce additional transcription factor-binding sequences, especially CTCF, at their insertion sites to generate species-specific TAD boundaries, and due to the participation in TAD evolution, CTCF binding motifs on pseudogenes were subjected to significantly heightened selection pressure. Deleting these pseudogenes in human embryonic stem cells (hESCs) disrupted the structure of species-specific TADs, whereas inserting them in mouse embryonic stem cells (mESCs) mediated new TADs formation, and pseudogenes involved in three-dimensional (3D) genome formation were critical for maintaining hESCs self-renewal. The structural necessity and biological function of these pseudogenes demonstrated the broad significance of pseudogenes in 3D genome construction and evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297131 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Three-dimensional genome structure plays an important role in gene regulation. Globally chromosomes are organized into active and inactive compartments, while at the gene level looping interactions connect promoters to regulatory elements. Topologically Associating Domains (TADs), typically several hundred kilobases in size form an intermediate level of organization. Major questions include how TADs are formed and what their relation is with looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb region on chromosome 7 surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Further, we find that these TAD boundaries are present irrespective of expression and looping of genes located between them. In contrast looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell type-specific long-range interactions and gene regulation. We investigated a 2.8 Mb region on Chromosome 7 (hg18 chr7: 115797757-118405450) containing the ENCODE region ENm001 42. The 5C experiment was designed to interrogate looping interactions between HindIII fragments containing transcription start sites (TSSs) and any other HindIII restriction fragment (distal fragments) in the target region. Libraries were generated for five cell lines: Caco2, Calu3, Capan1, GM12878 and HepG2, with two biological replicates for each line. 5C probes were designed at HindIII restriction sites (AAGCTT) using 5C primer design tools previously developed and made publicly available online at our My5C website (http://my5C.umassmed.edu). Probes were designed based on the ENCODE manual region 1 (ENM001) design 25 with additional probes placed throughout the region when appropriate. We also added probes to extend the analysis to include a 700 Kb gene desert region located directly adjacent to ENM001. Probe settings were: U-BLAST, 3; S-BLAST, 100; 15-MER, 3,000; MIN_FSIZE, 250; MAX_FSIZE, 20,000; OPT_TM, 65; OPT_PSIZE, 40. We designed 74 reverse 5C probes, and 605 forward 5C probes.

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Pseudogenes contribute to the evolution of topological domains across species via forming three-dimensional genome [hESC_KO_Hi-C]

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