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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [PRO-seq]

ABSTRACT: RNA polymerase II inhibition triggers a cellular stress response that paradoxically leads to the overexpression of certain transcripts. To investigate the underlying mechanism, we conducted genome-wide assays in human cells treated with triptolide, which disrupts the translocase/DNA helicase activity of XPB, part of TFIIH. Our analysis revealed that XPB activity-independent transcription of genes originate from thermodynamically unstable promoters. Among the upregulated genes, we identified three novel regulatory lncRNAs—TILR-1, TILR-2, and LINC00910 that are highly conserved among primates. Their expression is interdependent, and together, they regulate the nearby BRCA1 locus transcription. We observed that this network of transcripts is also activated in other stress responses, like heat shock and arsenic. We suggest that the BRCA1 locus and its lncRNAs regulators are part of a transcriptional switch that respond to broad stress conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299949 | GEO | 2025/10/01

REPOSITORIES: GEO

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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [s]

Project description:RNA polymerase II inhibition triggers a cellular stress response that paradoxically leads to the overexpression of certain transcripts. To investigate the underlying mechanism, we conducted genome-wide assays in human cells treated with triptolide, which disrupts the translocase/DNA helicase activity of XPB, part of TFIIH. Our analysis revealed that XPB activity-independent transcription of genes originate from thermodynamically unstable promoters. Among the upregulated genes, we identified three novel regulatory lncRNAs—TILR-1, TILR-2, and LINC00910 that are highly conserved among primates. Their expression is interdependent, and together, they regulate the nearby BRCA1 locus transcription. We observed that this network of transcripts is also activated in other stress responses, like heat shock and arsenic. We suggest that the BRCA1 locus and its lncRNAs regulators are part of a transcriptional switch that respond to broad stress conditions.

2025-10-01 | GSE299951 | GEO

Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [ChIP-exo]

2025-10-01 | GSE299950 | GEO

Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [RNA-Seq]

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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [s]

Project description:Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [s]

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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [RNA-Seq]

Project description:Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [RNA-Seq]

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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [ChIP-exo]

Project description:Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [ChIP-exo]

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Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [PRO-seq]

Project description:Highly-conserved lncRNAs regulates the BRCA1 locus under broad-stress responses [PRO-seq]

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Dysregulation of lncRNAs and circRNAs in mouse testes after exposure to triptolide

Project description:Triptolide has been shown to exert various pharmacological effects on systemic autoimmune diseases and cancers. However, its severe toxicity, especially reproduction toxicity, prevents wide clinical use for those people with fertility needs. Noncoding RNAs including lncRNAs and cicrRNAs are regulatory molecules that mediate a wide variety of physiological activities, which are critical for spermatogenesis, and their dysregulation might lead to male infertility. However, whether they are involved in triptolide-induced reproduction toxicity is fully unknown. Here, after exposure of mice to triptolide for 35 day, the total RNAs were used to investigate lncRNAs/cicrRNAs/mRNAs expression profiles by strand-specific RNA sequencing at the transcriptome level to help determine any RNA-related mechanisms in triptolide-induced toxicity. The results showed that triptolide significantly decreased the testicular weight, damaged testis and sperm morphology, reduced sperm motility and density. Furthermore, there's a remarkable deformity in sperm head and tail in triptolide-exposed mice. At the transcriptome level, the triptolide-treated mice exhibited aberrant expression profiles for lncRNAs/cicrRNAs/mRNAs, many of them were dysregulated. Gene ontology and pathway analyses revealed that the functions of differentially expressed lncRNA targets, cicrRNAs cognate genes and mRNAs were closely linked with many processes involved in spermatogenesis. Additionally, many newly identified lncRNAs /cicrRNAs displayed inducible expression, suggesting that they might be good candidate markers for triptolide-induced male reproductive toxicity. This study gives us an insight into understanding the reproductive system toxicity of triptolide and reminds us to strengthen the research on increasing efficacy and decreasing toxicity of triptolide.

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Systematic mutagenesis identifies p52/Tfb2 residues required for XPB/Ssl2 function within TFIIH and genetic interactions with TFB6

Project description:TFIIH is an evolutionarily conserved complex that plays central roles in both RNA polymerase II (pol II) transcription and DNA repair. As an integral component of the pol II Pre-Initiation Complex, TFIIH regulates the activity of the pol II enzyme in numerous ways. One of the essential functions of TFIIH resides in its XPB/Ssl2 subunit. XPB/Ssl2 is an ATP-dependent DNA translocase that stimulates promoter opening prior to transcription initiation. Crosslinking-mass spectrometry and cryo-EM results have shown a conserved interaction network involving XPB/Ssl2 and the C-terminal Hub region of the p52/Tfb2 core subunit. Here, we systematically mutagenized the HubA region of Tfb2 and screened for growth phenotypes in a TFB6 deletion background in Saccharomyces cerevisiae. We identified six lethal and twelve conditional mutants. Growth phenotypes of all but three of the conditional mutants were suppressed in the presence of Tfb6, thus identifying a functional interaction between Tfb2 HubA mutants and Tfb6, a protein that dissociates Ssl2 from TFIIH. Biochemical analysis of p52/Tfb2 mutants with severe growth phenotypes revealed defects in XPB/Ssl2 association. Further characterization of these Tfb2 mutant cells revealed defects in induction of Gal genes, and reduced occupancy TFIIH and pol II at Gal gene promoters, suggesting that functional TFIIH is required for proper Pol II recruitment to PICs in vivo. Consistent with recent structural models of TFIIH, our results identify key residues in the p52/Tfb2 HubA domain that are required for stable incorporation of XPB/Ssl2 into TFIIH, and for pol II transcription.

2022-06-30 | GSE196069 | GEO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell lines treated with triptolide for 6 or 16h - H3K27ac CUT&RUN

Project description:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer affecting young women and girls. Survival rates remain poor despite aggressive treatment of these patients with high-dose chemotherapy and radiation. SCCOHT is driven by loss of both SWI/SNF ATPases SMARCA4 and SMARCA2. Loss of SWI/SNF complex activity alters chromatin state, particularly at enhancers, which is believed to be crucial for oncogenesis. Super-enhancers are a distinct subset of enhancer clusters frequently associated with oncogenes in cancer. Here we discovered key distinctions between SWI/SNF binding following SMARCA4 restoration at enhancer vs. super-enhancer sites and characterized putative oncogene expression driven by super-enhancer activity. We found high sensitivity of SCCOHT cell lines to triptolide, a small molecule derived from the naturally occurring "thunder god vine" (Tripterygium wilfordii) that targets the XPB subunit of the transcription factor II H (TFIIH) complex, found at super-enhancers. Triptolide inhibits expression of many super-enhancer associated genes, and in particular, oncogenes. Notably, SALL4 expression, which is high in SCCOHT relative to other ovarian cancers and normal cell types, is significantly decreased following short triptolide treatment. In SCCOHT patient-derived xenograft models, triptolide and its prodrug derivative minnelide are particularly effective in inhibiting tumor growth. These results demonstrate the key oncogenic role of super-enhancer activity following epigenetic dysfunction in SCCOHT, which can be effectively targeted through inhibition of its functional components, such as TFIIH inhibition with triptolide.

2025-01-04 | GSE232745 | GEO

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