RNA surveillance controls 3D genome structure via stable cohesin-chromosome interaction

Abstract

The 3D architecture that the genome is folded into is regulated by CTCF, which determines domain borders, and cohesin, which generates interactions within domains. However, organisms lacking CTCF have been reported to still have cohesin-mediated 3D structures with strong borders. How this can be achieved and precisely regulated are yet unknown. Using in situ Hi-C, we found that 3'-end RNA processing factors coupled with proper transcription termination are a cis-acting determinant that regulates the localization and dynamics of cohesin on the chromosome arms. Loss of RNA processing factors, including nuclear exosome and Pfs2, destabilizes cohesin from the 3'-ends of convergent genes and results in decreased cohesin-mediated domain boundaries. We observed the co-localization between Rad21 and a wide range of 3'end RNA processing/termination factors. Further, deletion of Rrp6 leads to cohesin redistribution to facultative heterochromatin, resulting in improper domain boundaries. Importantly, we observed that knockdown of Rrp6/Exosc10 caused a defect in cohesin binding and loss of local topologically associating domains (TADs) interactions in mouse embryonic stem cells. Based on these findings, we propose a novel function of the RNA surveillance pathway in 3D genome organization via cohesin complex, which provides the molecular basis underlying the dynamics of cohesin function.

EXOSC10/Rrp6 is essential for the eight-cell embryo/morula transition

“…Our immunofluorescence data reveal that in blastomeres from the two-cell embryo stage onward EXOSC10 localizes to the periphery of NPBs and to the nucleus, while the protein appears to diffuse into the cytoplasm in oocytes and metaphase blastomeres that lack J o u r n a l P r e -p r o o f structured nuclei. Localization to the NPB is in agreement with the protein's well established function in ribosomal RNA processing (Davidson et al, 2019;Kent et al, 2009) and may point to a potential role in establishing chromatin domains (Chun et al, 2021;Fulka and Aoki, 2016). A critical role for EXOSC10 during cell growth and division via controlling protein translation is also supported by work on the anti-cancer drug 5-FU.…”

“…Moreover, mice lacking the NPBassociated ribosome biogenesis factor PES1 also show an early phenotype by failing to progress normally through the eight-cell embryo/morula/blastocyst steps (Lerch-Gaggl et al, 2002). In addition to impaired ribosome biogenesis, it is conceivable that altered RNA exosome-dependent and cohesin-mediated genome architecture also contributes to Exosc10's embryonic lethal phenotype (Chun et al, 2021). This is a tempting idea in the context of earlier findings that implicate NPBs and nucleoli in the spatial organization of the genome; reviewed in (Fulka and Aoki, 2016;Kresoja-Rakic and Santoro, 2019).…”

RNA processing mechanisms contribute to genome organization and stability in B cells

“…Furthermore, R-loops accumulate and cohesin localization at CBEs is altered, suggesting that DNA:RNA hybrids slow down cohesin scanning and stabilization at these sites, ultimately leading to genome disorganization [ 13 ]. Another study suggests cohesin and TAD boundary loss in the absence of RNA processing by the RNA exosome [ 54 ], while R-loops were recently shown to directly slow down cohesin progression, leading to decreased DNA compaction [ 55 ]. The kinetics of R-loop formation and resolution by RNA processing therefore appear critical for loop extrusion (Fig.…”

Pervasive RNA Binding Protein Enrichment on TAD Boundaries Regulates TAD Organization

“…AGO1 also binds at active enhancer regions which is eRNA dependent. It is recently demonstrated that 3'end RNA processing factors, including nuclear exosome and Pfs2, co-localize with cohesin and facilitate the 3D genome organization in both yeast and mESCs [28]. These individual based studies highlight the previously unaware participation of these RBPs in 3D genome organization; However, many questions remain to be answered, for example, what are the underlying mechanisms?…”