CTCF near nuclear speckles alters RNA processing in senescent cells
CTCF near nuclear speckles alters RNA processing in senescent cells
On July 21, Spyros Palikaras and colleagues published a study describing how human cells establish senescence, a stable arrest of cell division. In cultured cells, clusters of CTCF formed near nuclear speckles. Disrupting these clusters altered the RNA repertoire and delayed cell cycle arrest.
A senescent cell stops dividing but continues to change how its genes operate. A single gene can produce several forms of messenger RNA, each of which provides instructions for making a protein. Splicing removes and joins segments of the initial RNA transcript, determining which form is produced. Senescent cells develop a distinct and stable repertoire of these RNA forms.
The nucleus contains nuclear speckles, regions where RNAs and proteins involved in splicing accumulate. CTCF helps fold DNA into loops and separates neighboring regions of chromosomes. The authors found that CTCF forms clusters near nuclear speckles as cells enter senescence.
The experiments used human IMR90 lung fibroblasts. The researchers compared chemically induced senescence with cells that had aged through repeated division. Earlier work from the same research program linked the onset of senescence to the departure of HMGB2 from the nucleus and the clustering of CTCF. The new study adds BANF1, which contributes to chromosome organization, and SRRM2, a component of nuclear speckles, to this sequence of events.
In this cell model, the loss of HMGB2 changes DNA organization. CTCF and BANF1 then reorganize DNA near nuclear speckles, while SRRM2 connects this reorganization to RNA processing. When the researchers disrupted CTCF clusters, the RNA isoform repertoire associated with senescence returned almost to the state found in dividing cells, and the cells stopped dividing later.
The authors also observed age-related changes in this program in skin fibroblasts from donors of different ages and in whole-blood data.