Alpha satellite RNA marks the perinucleolar compartment and represses ribosomal RNA expression in naïve human embryonic stem cells

Model for the role of ALR RNA in naïve human ESCs

Authors: Mittal K, Ataei L, Ramalho-Santos M.

Genes and Development, 2026. doi: 10.1101/gad.353162.125

PMID: 41730687

Abstract: While most newly synthesized RNA is exported to the cytoplasm, a portion of noncoding RNA is retained in the nucleus and remains highly associated with chromatin. The strong binding of this RNA fraction to insoluble chromatin impairs its recovery in standard transcriptomic studies. Therefore, the landscape and potential functions of chromatin-associated RNAs are poorly understood. Recent studies indicate that chromatin-associated transcripts can have regulatory roles, particularly during mammalian development. Here we compare the dynamics of cytoplasmic versus chromatin-bound transcriptomes of naive and primed human embryonic stem cells (hESCs) as well as fibroblasts. We found a remarkable enrichment for RNA transcribed from α-satellite repeat (ALR) in the chromatin fraction of naive hESCs compared with primed hESCs. The colocalization and interaction of ALR RNA with polypyrimidine tract binding protein 1 (PTBP1) and CUG-binding protein (CUGBP) indicate that ALR RNA foci mark the perinucleolar compartment (PNC), a nuclear subcompartment previously thought to be exclusive to cancer cells. Knockdown of ALR RNA leads to dispersion of PTBP1/CUGBP foci, upregulation of ribosomal RNA, and global hypertranscription in naive hESCs. In contrast, loss of PTBP1 does not disturb ALR RNA localization, indicating that ALR is upstream in the hierarchy of organization of the PNC in hESCs. These results reveal a role for ALR RNA in nuclear compartmentalization and tuning rRNA synthesis in naive hESCs. Moreover, this study opens new avenues to dissect the function of ALR RNA and the PNC in cancer contexts.