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Pseudogenes contribute to the evolution of topological domains across species via forming three-dimensional genome [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 functional unknown. Here, we found that DNA sequence of pseudogenes can form chromatin contacts, acting as anchors of chromatin loops and boundaries of topological associated domains (TADs), many of them are proved to be structural important and essential for human embryonic stem cells (hESCs) survival. Incorporating genetic data, we defined a hominoidea-specific pseudogene, TUBBP2, which acted as a TAD boundary by enriching CTCF, to maintain the 3D genome and self-renewal of hESCs. Evolutionally, TUBBP2 was generated in 18.8 million years ago through retroposition and inherited the CTCF binding motif from its parent gene-TUBB, thus enhance the strength of TADs at the insertion site in great apes genome. More amazing, by inheritance from parent genes or sequence variation, a part of pseudogenes can introduce additional CTCF binding sequence at their insertion sites to generate species-specific topological domains, which may contribute to species evolution. Overall, we not only demonstrate the essentiality of pseudogenes in the formation and maintenance of 3D chromatin structure, but provide insights on their functions of driving species evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246661 | GEO | 2025/10/01

REPOSITORIES: GEO

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

Project description: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 functional unknown. Here, we found that DNA sequence of pseudogenes can form chromatin contacts, acting as anchors of chromatin loops and boundaries of topological associated domains (TADs), many of them are proved to be structural important and essential for human embryonic stem cells (hESCs) survival. Incorporating genetic data, we defined a hominoidea-specific pseudogene, TUBBP2, which acted as a TAD boundary by enriching CTCF, to maintain the 3D genome and self-renewal of hESCs. Evolutionally, TUBBP2 was generated in 18.8 million years ago through retroposition and inherited the CTCF binding motif from its parent gene-TUBB, thus enhance the strength of TADs at the insertion site in great apes genome. More amazing, by inheritance from parent genes or sequence variation, a part of pseudogenes can introduce additional CTCF binding sequence at their insertion sites to generate species-specific topological domains, which may contribute to species evolution. Overall, we not only demonstrate the essentiality of pseudogenes in the formation and maintenance of 3D chromatin structure, but provide insights on their functions of driving species evolution.

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Project description: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.

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Modeling of DNA methylation in cis reveals principles of chromatin folding in vivo in the absence of crosslinking and ligation

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High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion [HiChIP]

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