An alternative transcription factor isoform controls AML chemoresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1139820 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR29969352_1.fastq.gz | Fastqsanger.gz | |||
| SRR29969352_2.fastq.gz | Fastqsanger.gz | |||
| SRR29969353_1.fastq.gz | Fastqsanger.gz | |||
| SRR29969353_2.fastq.gz | Fastqsanger.gz |
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Project description:An alternative transcription factor isoform controls AML chemoresistance [LongRead_mRNA]
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Project description:Aberrant splicing is a hallmark of many cancers, including Acute Myeloid Leukemia (AML), but its role in post-treatment relapse remains poorly understood. Here, we analyzed the alternative splicing landscape of 19 AML patients during chemotherapy treatment. We found an upregulation of the long isoform of the transcription factor RUNX1 (also known as RUNX1C) in relapsed cohorts, which conferred chemotherapy resistance. Notably, these patients showed elevanted intragenic DNA methylation at the RUNX1 proximal promoter, thereby activating RUNX1C transcript through its alternative distal promoter. Mechanistically the N-terminus region of RUNX1C is required to promote chemoresistance by regulating a distinct RUNX1 transciptional program. Among these target genes, B-cell translocation gene 2 (BTG2) mediates a quiescent-like phenotype by deadenylating ribosomal RNAs to reduce global protein synthesis. Lastly, we harnessed orthogonal RNA-targeting strategies to target RUNX1C isoform, which led to augmented chemotherapy efficacy. Collectively, our finidngs delineate a transcriptional circuity orchestrated by a transcription factor isoform that underpins chemotherapy responsiveness and a potential therapeutic strategy to mitigate disease recurrence.
2025-05-29 | GSE273034 | GEO
Project description:Aberrant splicing is a hallmark of many cancers, including Acute Myeloid Leukemia (AML), but its role in post-treatment relapse remains poorly understood. Here, we analyzed the alternative splicing landscape of 19 AML patients during chemotherapy treatment. We found an upregulation of the long isoform of the transcription factor RUNX1 (also known as RUNX1C) in relapsed cohorts, which conferred chemotherapy resistance. Notably, these patients showed elevanted intragenic DNA methylation at the RUNX1 proximal promoter, thereby activating RUNX1C transcript through its alternative distal promoter. Mechanistically the N-terminus region of RUNX1C is required to promote chemoresistance by regulating a distinct RUNX1 transciptional program. Among these target genes, B-cell translocation gene 2 (BTG2) mediates a quiescent-like phenotype by deadenylating ribosomal RNAs to reduce global protein synthesis. Lastly, we harnessed orthogonal RNA-targeting strategies to target RUNX1C isoform, which led to augmented chemotherapy efficacy. Collectively, our finidngs delineate a transcriptional circuity orchestrated by a transcription factor isoform that underpins chemotherapy responsiveness and a potential therapeutic strategy to mitigate disease recurrence.
2025-05-29 | GSE273359 | GEO
Project description:Aberrant splicing is a hallmark of many cancers, including Acute Myeloid Leukemia (AML), but its role in post-treatment relapse remains poorly understood. Here, we analyzed the alternative splicing landscape of 19 AML patients during chemotherapy treatment. We found an upregulation of the long isoform of the transcription factor RUNX1 (also known as RUNX1C) in relapsed cohorts, which conferred chemotherapy resistance. Notably, these patients showed elevanted intragenic DNA methylation at the RUNX1 proximal promoter, thereby activating RUNX1C transcript through its alternative distal promoter. Mechanistically the N-terminus region of RUNX1C is required to promote chemoresistance by regulating a distinct RUNX1 transciptional program. Among these target genes, B-cell translocation gene 2 (BTG2) mediates a quiescent-like phenotype by deadenylating ribosomal RNAs to reduce global protein synthesis. Lastly, we harnessed orthogonal RNA-targeting strategies to target RUNX1C isoform, which led to augmented chemotherapy efficacy. Collectively, our finidngs delineate a transcriptional circuity orchestrated by a transcription factor isoform that underpins chemotherapy responsiveness and a potential therapeutic strategy to mitigate disease recurrence.
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Project description:Chemoresistance remains a major obstacle to the successful treatment of breast cancer. Especially, more than 80% of cases cannot achieve pathological complete response (pCR) in patients who received neoadjuvant chemotherapy (NAC). Understanding the mechanisms involved in chemoresistance can guide the development of efficient therapies in patients with breast cancer. Herein, we identified a novel p62 isoform with a short 3′UTR (p62-SU, 662-nt) that is associated with chemoresistance by RNA-sequence and verified by qRT-PCR, 3′RACE, and northern blot in breast cancer cells and tissue specimens. Furthermore, enforced expression of p62-SU dramatically promoted the ability of proliferation, migration, invasion, and chemoresistance compared with p62 isoform with a long/full-length 3′UTR (p62-LU, 1485-nt) in vivo and in vitro. Mechanistically, we revealed that CPSF1 could regulate the 3′UTR shorting of p62 by alternative polyadenylation and then enhanced chemoresistance in breast cancer cells. In addition, we found that p62-SU escaped the repression of miR-124-3p and promoted the ability of p62-SU to produce more protein and, subsequently, p62-dependent chemoresistance. Together, our data suggest the p62-SU, generated by CPSF1, plays an essential role in the regulation of breast cancer chemoresistance through CPSF1-p62-miR-124-3p signaling.
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Project description:Through alternative processing of pre-mRNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes based on deep sequencing of cDNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analysis of mappings of sequence reads to exon-exon junctions indicated that ~94% of human genes undergo alternative splicing (AS), ~86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that a majority of AS and alternative cleavage and polyadenylation (APA) events exhibit variation between tissues. Variations in alternative mRNA isoform expression between 6 individuals were also detected in cerebellar cortex, with ~2- to 3-fold less isoform variation observed between individuals than between tissues. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation and with generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation, and sequence conservation of known regulatory motifs in both regulated introns and 3' UTRs suggested common involvement of the same factors in regulation of tissue-specific splicing and polyadenylation. Exam mRNA expression in 15 human tissues and cell lines
2008-09-30 | E-GEOD-12946 | biostudies-arrayexpress
Project description:An alternatively spliced p62 isoform promotes breast cancer chemoresistance
| PRJNA812680 | ENA
Project description:Through alternative processing of pre-mRNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes based on deep sequencing of cDNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analysis of mappings of sequence reads to exon-exon junctions indicated that ~94% of human genes undergo alternative splicing (AS), ~86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that a majority of AS and alternative cleavage and polyadenylation (APA) events exhibit variation between tissues. Variations in alternative mRNA isoform expression between 6 individuals were also detected in cerebellar cortex, with ~2- to 3-fold less isoform variation observed between individuals than between tissues. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation and with generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation, and sequence conservation of known regulatory motifs in both regulated introns and 3' UTRs suggested common involvement of the same factors in regulation of tissue-specific splicing and polyadenylation.
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Project description:SIRT3 deacetylase is a critical mitochondrial regulator for mitochondrial metabolism reprogramming and ROS production, and is involved in the regulation of chemoresistance in AML. SIRT3 is a SUMOylated protein, with de-SUMOylation by SENP1, resulted in enhancement of its deacetylase activity. However, the molecular mechanism of de-SUMOylation mediated SIRT3 activation, which may lead to reinforced AML chemoresistance, remains poorly understood. In the current study, we demonstrated that SIRT3 SUMOylation was attenuated by cytarabine, and de-SUMOylation prevented SIRT3 from proteasome degradation. SIRT3 de-SUMOylation was capable of reprogramming mitochondrial biogenesis, and subsequently inhibited mitochondrial ROS production. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation, among which the transcription factor HES1, a downstream substrates of Notch1 signaling pathway, was significantly downregulated by SIRT3K288R, the de-SUMOylated and constitutively active mutant of SIRT3. HES1-dependent FAO was inhibited by SIRT3 de-SUMOylation. Moreover, cytarabine synergized with the SENP1 inhibitor momodrin-Ic to eradicate AML blasts in vitro and in xenografts mice models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in regulating chemoresistance in AML via HES1-dependent FAO, which may provide a rationale for SIRT3 SUMOylation-targeted intervention to improve the chemotherapies in AML.
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