RNA promotes the formation of spatial compartments in the nucleus
Quinodoz SA, Jachowicz JW, Bhat P, Ollikainen N, Banerjee AK, Goronzy IN, Blanco MR, Chovanec P, Chow A, Markaki Y, Thai J, Plath K, Guttman M. RNA promotes the formation of spatial compartments in the nucleus. Cell. 2021 Nov 11;184(23):5775-5790.e30. doi: 10.1016/j.cell.2021.10.014. Epub 2021 Nov 4. PMID: 34739832; PMCID: PMC9115877.
The process of transcription can affect the formation of nuclear spatial compartments. Using RNA and DNA SPRITE to map RNA including pre-mRNAs, ncRNAs they study how RNA mediates nuclear compartmentalization.
The process involves three steps:
Seeding: nuclear RNA builds up concentrations close to where they were transcribed
Binding: they bind diffusible ncRNA and proteins
Recruiting: change the distribution of these diffusible molecules to preferentially enrich them within precise high-concentration areas.
By recruiting diffusible regulatory factors to multiple DNA sites, these ncRNAs may also act to drive coalescence of distinct DNA regions into a shared territory in the nucleus… RNA may represent a widespread class of molecules that act as seeds to drive spatial organization of diffusible molecules.
Why RNA
This precise spatial behaviour is possible because RNA is unlike proteins and DNA - proteins form through translation in the cytoplasm and have no nuclear location information; DNA is singular and cannot accumulate. Further, ncRNAs are unlike mRNA, which needs translation and does interact with regulators in the nucleus. However, RNA with function independent of their translated product can have similar effects:
histone pre-mRNAs can seed organization of nuclear compartments even though their processed RNAs are also translated into protein products.
lncRNAs (93%) are enriched near their transcriptional loci while mature mRNAs are depleted. These are some lncRNAs that, despite high enrichment, are not restricted to their transcriptional loci. lncRNAs were shown more stable than nascent pre-mRNA, comparable to the stability of mature mRNA, even after transcriptional inhibition.
Inhibiting the formation of nascent RNA showed no structural changes in chromosome territories or A/B compartments but, in the nuclear structures associated with ribosome, snRNA and histone biogenesis, it did disrupt DNA and RNA organization.
ncRNA processing hubs around DNA that encodes their nascent targets
They found that “ncRNAs form processing hubs around genomic DNA encoding their nascent targets”:
ncRNAs involved in ribosomal RNA processing organize around transcribed ribosomal RNA genes
ncRNAs involved in mRNA splicing are spatially concentrated around genes containing a high density of Pol II
ncRNAs involved in snRNA biogenesis are organized around snRNA gene clusters
The histone processing U7 snRNA is enriched around histone gene loci
ncRNAs influence gene expression regulation
Hundreds of lncRNAs are enriched in ‘territories’ in the nucleus and affect protein localization within them. Proteins may bind to ncRNAs and get localized to their territories. This recruitment, depending on what’s recruited, can affect gene expression within the territory.