H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2.
Cancer Gene Ther
; 31(8): 1177-1185, 2024 Aug.
Article
de En
| MEDLINE
| ID: mdl-38811797
ABSTRACT
RNA processing is an essential post-transcriptional phenomenon that provides the necessary complexity of transcript diversity prior to translation. Aberrations in this process could contribute to tumourigenesis, and we have previously reported increased splicing alterations in giant cell tumor of bone (GCTB), which carries mutations in the histone variant H3.3 encoding glycine 34 substituted for tryptophan (H3.3-G34W). G34W interacts with several splicing factors, most notably the trans-acting splicing factor hnRNPA1L2. To gain a deeper understanding of RNA processing in GCTB and isogenic HeLa cells with H3.3-G34W, we generated RNA-immunoprecipitation sequencing data from hnRNPA1L2 and H3.3-G34W associated RNAs, which showed that 80% overlapped across genic regions and were frequently annotated as E2F transcription factor binding sites. Splicing aberrations in both GCTB and HeLa cells with H3.3-G34W were significantly enriched for known hnRNPA1L2 binding motifs (p value < 0.01). This splicing aberration differed from hnRNPA1L2 knockouts, which showed alterations independent of H3.3-G34W. Of functional significance, hnRNPA1L2 was redistributed to closely match the H3.3 pattern, likely driven by G34W, and to loci not occupied in normal parental cells. Taken together, our data reveal a functional overlap between hnRNPA1L2 and H3.3-G34W with likely significant consequences for RNA processing during GCTB pathogenesis. This provides novel opportunities for therapeutic intervention in future modus operandi.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs osseuses
/
Histone
/
Exons
/
Tumeur osseuse à cellules géantes
Limites:
Humans
Langue:
En
Journal:
Cancer Gene Ther
/
Cancer gene ther
/
Cancer gene therapy
Sujet du journal:
GENETICA MEDICA
/
NEOPLASIAS
/
TERAPEUTICA
Année:
2024
Type de document:
Article
Pays de publication:
Royaume-Uni