Amazing stuff!
"Temporarily disabling a protein complex [cohesin] that organizes DNA into loops inside the cell’s nucleus drastically disrupted the three-dimensional structure of the genome, but surprisingly most genes continued to function as usual ...
However, they also discovered a small group of affected genes that play a critical role in guiding cells to become specific types, for example heart, brain or liver cells. ...
The protein complex, called cohesin, plays a key role in shaping the three-dimensional structure of DNA inside the nucleus. This organization not only helps DNA fit inside the nucleus but brings distant regulatory elements into contact with the genes they control, influencing which genes are turned on or off to maintain cell identity and function.
Intriguingly, previous research suggested that removing cohesin – and the loops it forms – had little effect on overall gene activity. At the same time, mutations in cohesin are commonly found in cancers and in disorders, known as cohesinopathies, that affect physical and cognitive development.
The researchers revisited the interplay between cohesin and gene activity employing stem cells in a unique experimental system. ...
When the researchers removed cohesin at that point [post mitosis], they confirmed that it is essential for maintaining how the DNA is folded. Without cohesin, the overall genomic structure was severely disrupted, with most DNA loops failing to re-form, as shown by techniques that map different DNA interactions in three dimensions. ..."
From the abstract:
"Acute cohesin loss causes widespread reorganization of three-dimensional (3D) chromatin architecture but has relatively minor effects on steady-state transcription.
It remains unclear whether its role in gene regulation becomes more critical during mitotic exit, when 3D chromatin architecture and transcription are globally re-established.
To address this, we acutely depleted RAD21 in mouse embryonic stem cells during mitotic exit under self-renewal or differentiation conditions.
Here we show that, although most loops failed to reform without cohesin, the few cohesin-independent loops were linked to active promoters, strong enhancers and H3K27ac mitotic bookmarking.
Transcriptional changes were only modest, indicating that gene reactivation largely bypasses cohesin. Sensitive genes showed RAD21 promoter binding, a higher number of structural loops and positioning within well-insulated, gene-poor topologically associating domains.
During differentiation, cohesin loss impaired activation of a broader set of developmental genes, partly due to defective de novo regulatory interactions. Together, these findings demonstrate context-specific requirements for cohesin in gene activation."
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