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Linker histone variant H1-10 promotes prostate cancer proliferation [RNA-seq]

ABSTRACT: While the linker histone H1 is recognized for its role in stabilizing higher-order chromatin structures, the distinct functions of its variants remain underexplored. In this study, we uncover that the H1-10 is markedly overexpressed in prostate cancer and associates with a poor prognosis. H1-10 is mainly localized to the nucleolus, where it facilitates nucleolar assembly through liquid condensation. H1-10 amplifies ribosomal RNA (rRNA) transcription by directly associating with RNA polymerase I (Pol I), thereby enhancing Pol I binding affinity for ribosomal DNA (rDNA). This results in expanded production of rRNA and elevated global protein translation. By further investigation, we found that H1-10 boosts the protein translation of transcription factor E2F3, which in turn induces the transcription of cell growth genes by increasing the level of CTD serine 5 phosphorylated RNA polymerase II at gene promoters. Critically, through high-throughput virtual screening, we identified specific small molecules that inhibit H1-10 by targeting its DNA binding domain. On-target validations showed these molecules blocked H1-10-mediated Pol I rDNA occupancy, global protein translation and prostate tumor growth in vitro and in vivo. In summary, our study reveals the critical role of H1-10 in ribosome biogenesis and prostate cancer progression, and pioneers the pharmacological targeting of an H1 variant, highlighting the therapeutic promise of targeting histone variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270159 | GEO | 2026/05/06

REPOSITORIES: GEO

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Small molecules targeting histone variant H1-10

Project description:While the linker histone H1 is recognized for its role in stabilizing higher-order chromatin structures, the distinct functions of its variants remain underexplored. In this study, we uncover that the H1-10 is markedly overexpressed in prostate cancer and associates with a poor prognosis. H1-10 is mainly localized to the nucleolus, where it facilitates nucleolar assembly through liquid condensation. H1-10 amplifies ribosomal RNA (rRNA) transcription by directly associating with RNA polymerase I (Pol I), thereby enhancing Pol I binding affinity for ribosomal DNA (rDNA). This results in expanded production of rRNA and elevated global protein translation. By further investigation, we found that H1-10 boosts the protein translation of transcription factor E2F3, which in turn induces the transcription of cell growth genes by increasing the level of CTD serine 5 phosphorylated RNA polymerase II at gene promoters. Critically, through high-throughput virtual screening, we identified specific small molecules that inhibit H1-10 by targeting its DNA binding domain. On-target validations showed these molecules blocked H1-10-mediated Pol I rDNA occupancy, global protein translation and prostate tumor growth in vitro and in vivo. In summary, our study reveals the critical role of H1-10 in ribosome biogenesis and prostate cancer progression, and pioneers the pharmacological targeting of an H1 variant, highlighting the therapeutic promise of targeting histone variants.

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RNA helicase DDX21 coordinates transcription and noncoding RNA processing of the ribosomal pathway

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Low dose ribosomal DNA P-loop mutation affects development and enforces autophagy in Arabidopsis

Project description:Arabidopsis contains hundreds of ribosomal DNA copies organised within the nucleolar organising regions (NORs) in chromosomes 2 and 4. There are four major types of variants of rDNA, VAR1-4, based on the polymorphisms of 3' external transcribed sequences and these are variably expressed during plant development. We created a mutant by the CRISPR-Cas9-mediated excision of ~25 nt from only the copies of NOR4 ribosomal DNA, obtaining mosaic mutational events on ~5% of all rDNA copies. The excised region consist of P-loop and Helix-82 region of 25S rRNA. The mutation led to allelic, dosage-dependent defects marked by lateral root inhibition, reduced size, and pointy leaves typical of defective ribosomal function. The mutation in NOR4 led to dosage compensation from the NOR2 copies, marked by its associated single-nucleotide polymorphisms and, thus, resulted in an altered rRNA sub-population. Furthermore, it caused rRNA maturation defects specifically in the minor pathway characterised by 32S pre-rRNA accumulation. The mutated rRNAs were not incorporated into the translating ribosomes and, thus, the accompanying elevated autophagic flux was likely to be related to ribophagy.

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