“…To further explore the role of O-GlcNAcylation in FOXA1 transcriptional competency, the O-GlcNAcylation–modulated FOXA1 interactome, genome-wide binding sites, and target transcriptome were comprehensively analyzed. By characterizing the interactome of FOXA1 in different O-GlcNAcylation states, we showed that FOXA1 was unexpectedly associated with proteins that are components of DNA repair and mRNA spliceosome complexes, as previously reported ( 8 , 27 , 51 ). Since the association of FOXA1 and ERα and chromatin distribution of ERα are constant regardless of FOXA1 O-GlcNAcylation state, we excluded the possibility that O-GlcNAcylation is required for FOXA1-mediated ERα activation.…”
Section: Discussionsupporting
confidence: 77%
“…Networks of enriched FOXA1 interacting nuclear partners (interactome) were constructed, and Gene Ontology (GO) analysis showed that both FOXA1 WT and FOXA1 3A mutant partners were involved in terms related to RNA splicing, ribosome biogenesis, transcription, cell cycle, and DNA repair, which is consistent with previously known FOXA1 biological functions (8,27,28). FOXA1 WT -specific enriched proteins were associated with chromatin remodeling, epigenetic regulation, and DNA methylation processes, whereas predominant themes including apoptosis and response to stress were identified in the FOXA1 3A mutant interactome (Fig.…”
Section: O-glcnacylation Triggers a Rearrangement Of The Foxa1 Intera...supporting
FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-
N
-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr
432
, Ser
441
, and Ser
443
regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including
EPB41L3
and
COL9A2
. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.
“…To further explore the role of O-GlcNAcylation in FOXA1 transcriptional competency, the O-GlcNAcylation–modulated FOXA1 interactome, genome-wide binding sites, and target transcriptome were comprehensively analyzed. By characterizing the interactome of FOXA1 in different O-GlcNAcylation states, we showed that FOXA1 was unexpectedly associated with proteins that are components of DNA repair and mRNA spliceosome complexes, as previously reported ( 8 , 27 , 51 ). Since the association of FOXA1 and ERα and chromatin distribution of ERα are constant regardless of FOXA1 O-GlcNAcylation state, we excluded the possibility that O-GlcNAcylation is required for FOXA1-mediated ERα activation.…”
Section: Discussionsupporting
confidence: 77%
“…Networks of enriched FOXA1 interacting nuclear partners (interactome) were constructed, and Gene Ontology (GO) analysis showed that both FOXA1 WT and FOXA1 3A mutant partners were involved in terms related to RNA splicing, ribosome biogenesis, transcription, cell cycle, and DNA repair, which is consistent with previously known FOXA1 biological functions (8,27,28). FOXA1 WT -specific enriched proteins were associated with chromatin remodeling, epigenetic regulation, and DNA methylation processes, whereas predominant themes including apoptosis and response to stress were identified in the FOXA1 3A mutant interactome (Fig.…”
Section: O-glcnacylation Triggers a Rearrangement Of The Foxa1 Intera...supporting
FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-
N
-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr
432
, Ser
441
, and Ser
443
regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including
EPB41L3
and
COL9A2
. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.
“…Unlike T-ALL, the most prominent oncogenes for some of these cancers are less studied. However, as listed in detail in the Results section of this paper, we found existing literature support for some of the identified motifs, such as PU.1 (SPI1) [19–22], RUNX-related genes [21–24] and MYB gene family [22, 25–27] for AML, STAT1 [28], STAT5 [29], ASCL1 [30], for BRCA, for CRC, AP1 [31] for LUAD, and FOXA1 [32–35] and FOXP1 [36] for PRAD. Figures [6-10] demonstrates the distribution of distances between the CTCF-center and the motif site-center for the most significantly enriched motifs associated with AML, BRCA, CRC, LUAD, and PRAD, complemented by the representation of each motif’s sequence logos. Fig 6. The distribution of center-to-center distances between cancer-specific CTCF sites and sites of enriched motifs for AML. a. Violin plot for AML.…”
Section: Figmentioning
confidence: 86%
“…Unlike T-ALL, the most prominent oncogenes for some of these cancers are less studied. However, as listed in detail in the Results section of this paper, we found existing literature support for some of the identified motifs, such as PU.1 (SPI1) [19–22], RUNX-related genes [21–24] and MYB gene family [22, 25–27] for AML, STAT1 [28], STAT5 [29], ASCL1 [30], for BRCA, for CRC, AP1 [31] for LUAD, and FOXA1 [32–35] and FOXP1 [36] for PRAD.…”
Characterization of gene regulatory mechanisms in cancer is a key task in cancer genomics. CCCTC-binding factor (CTCF), a DNA binding protein, exhibits specific binding patterns in the genome of cancer cells and has a non-canonical function to facilitate oncogenic transcription programs by cooperating with transcription factors bound at flanking distal regions. Identification of DNA sequence features from a broad genomic region that distinguish cancer-specific CTCF binding sites from regular CTCF binding sites can help find oncogenic transcription factors in a cancer type. However, the long DNA sequences without localization information makes it difficult to perform conventional motif analysis. Here we present DNAResDualNet (DARDN), a computational method that utilizes convolutional neural networks (CNNs) for predicting cancer-specific CTCF binding sites from long DNA sequences, coupled with feature discovery using DeepLIFT for identifying DNA sequence features associated with cancer-specific CTCF binding. Evaluation on DNA sequences associated with CTCF binding sites in T-cell acute lymphoblastic leukemia (T-ALL) and other cancer types demonstrates DARDN’s ability in classifying DNA sequences surrounding cancer-specific CTCF binding from control constitutive CTCF binding and identifying sequence motifs for transcription factors potentially active in each specific cancer type. We identified potential oncogenic transcription factors in T-ALL, acute myeloid leukemia (AML), breast cancer (BRCA), colorectal cancer (CRC), lung adenocarcinoma (LUAD), and prostate cancer (PRAD). Our work demonstrates the power of advanced machine learning and feature discovery approach in finding biologically meaningful information from complex high-throughput sequencing data.
“…Conversely, alternative splicing yields multiple transcripts and protein isoforms from a single gene, 11 occasionally generating non‐coding RNAs as byproducts 11 . Alternative splicing augments gene expression complexity and protein function diversity, 12 contributing significantly to normal physiology while also being implicated in various diseases, such as Parkinson's disease, Alzheimer's disease, spinal muscular atrophy, familial dysautonomia, cystic fibrosis, Frasier syndrome and cancer initiation and progression 13,14 . In tumour cells, alternative splicing plays a crucial role in the development of diverse malignant phenotypes 15 .…”
BackgroundN6‐methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and recognised by m6A‐binding proteins. This modification significantly influences carious facets of RNA metabolism and plays a pivotal role in cellular and physiological processes.Main bodyPre‐mRNA alternative splicing, a process that generates multiple splice isoforms from multi‐exon genes, contributes significantly to the protein diversity in mammals. Moreover, the presence of crosstalk between m6A modification and alternative splicing, with m6A modifications on pre‐mRNAs exerting regulatory control, has been established. The m6A modification modulates alternative splicing patterns by recruiting specific RNA‐binding proteins (RBPs) that regulate alternative splicing or by directly influencing the interaction between RBPs and their target RNAs. Conversely, alternative splicing can impact the deposition or recognition of m6A modification on mRNAs. The integration of m6A modifications has expanded the scope of therapeutic strategies for cancer treatment, while alternative splicing offers novel insights into the mechanistic role of m6A methylation in cancer initiation and progression.ConclusionThis review aims to highlight the biological functions of alternative splicing of m6A modification machinery and its implications in tumourigenesis. Furthermore, we discuss the clinical relevance of understanding m6A‐dependent alternative splicing in tumour therapies.
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