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Updated: Jan 20, 2026
Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
Involvement of non-coding RNAs and transcription factors in the induction of Transglutaminase isoforms by ATRA
Ornella Franzese1, Linda Minotti2, Gianluca Aguiari3
1Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.
Abstract:
The multifunctional protein Transglutaminase type 2, is associated with cancer epithelial mesenchymal transition, invasiveness, stemness and drugs resistance. Several variant isoforms and non-coding RNAs are present in cancer and this report explored the expression of these transcripts of the TGM2 gene in cancer cell lines after induction with all-trans retinoic acid. The expression of truncated variants along with two long non-coding RNAs, was demonstrated. One of these is coded from the first intron and the Last Exon Variant is constituted by a sequence corresponding to the last three exons and the 3'UTR. Analysis of ChIP-seq data, from ENCODE project, highlighted factors interacting with intronic sequences, which could interfere with the progression of RNApol II at checkpoints, during the elongation process. Some relevant transcription factors, bound in an ATRA-dependent way, were found by RNA immunoprecipitation, notably GATA3 mainly enriched to Last Exon Variant non-coding RNA. The involvement of NMD in the regulation of the ratio among these transcripts was observed, as the prevalent recovering of Last Exon Variant to phUPF1-complexes, with decrease of the binding towards other selective targets. This study contributes to identify molecular mechanisms regulating the ratio among the variants and improves the knowledge about regulatory roles of the non-coding RNAs of the TGM2 gene.
Insights
This study investigates Transglutaminase type 2 (TGM2) gene variants and non-coding RNAs in cancer cells treated with all-trans retinoic acid (ATRA). It reveals molecular mechanisms regulating TGM2 transcript ratios and the role of non-coding RNAs.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Transglutaminase type 2 (TGM2) is a multifunctional protein implicated in cancer progression, including epithelial-mesenchymal transition, invasiveness, stemness, and drug resistance.
- The TGM2 gene exhibits diverse variant isoforms and non-coding RNAs in cancer, suggesting complex regulatory roles.
Purpose of the Study:
- To explore the expression of TGM2 gene transcripts, including variant isoforms and long non-coding RNAs, in cancer cell lines following all-trans retinoic acid (ATRA) induction.
- To elucidate the molecular mechanisms governing the ratio of these TGM2 transcripts and the regulatory functions of its non-coding RNAs.
Main Methods:
- Cancer cell lines were treated with all-trans retinoic acid (ATRA) to induce expression of TGM2 transcripts.
- Analysis of ENCODE ChIP-seq data identified factors interacting with intronic sequences affecting RNA polymerase II progression.
- RNA immunoprecipitation (RIP) was used to detect transcription factor binding, particularly GATA3, to the Last Exon Variant non-coding RNA in an ATRA-dependent manner.
- The involvement of the Nonsense-Mediated Decay (NMD) pathway in regulating transcript ratios was assessed by analyzing interactions with UPF1 complexes.
Main Results:
- The study demonstrated the expression of truncated TGM2 variants and two long non-coding RNAs (lncRNAs) after ATRA treatment.
- One lncRNA is coded from the first intron, and the Last Exon Variant (LEV) is composed of the last three exons and the 3'UTR.
- ATRA-dependent binding of transcription factors, notably GATA3 to the LEV lncRNA, was identified.
- The Nonsense-Mediated Decay (NMD) pathway was found to regulate transcript ratios, with preferential association of the LEV with UPF1 complexes.
Conclusions:
- This research identifies novel molecular mechanisms controlling the expression ratios of TGM2 gene variants and non-coding RNAs.
- The findings enhance the understanding of the regulatory roles played by TGM2 non-coding RNAs in cancer.
- The study highlights the potential involvement of TGM2 variants and lncRNAs in cancer progression and drug resistance, modulated by ATRA signaling.
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