Overlapping genes share same genomic regions in parallel (sense) or anti-parallel (anti-sense) orientations. These gene pairs seem to occur in all domains of life and are best known from viruses. ...However, the advantage and biological significance of overlapping genes is still unclear. Expressed sequence tags (ESTs) analysis enabled us to uncover an overlapping gene pair in the human genome.
By using in silico analysis of previous experimental documentations, we reveal a new form of overlapping genes in the human genome, in which two genes found on opposite strands (Pou5f1 and Tcf19), share two exons and one intron enclosed, at the same positions, between OCT4B3 and TCF19-D splice variants.
This new form of overlapping gene expands our previous perception of splicing events and may shed more light on the complexity of gene regulation in higher organisms. Additional such genes might be detected by ESTs analysis also of other organisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OCT4 plays critical roles in self-renewal and pluripotency maintenance of embryonic stem cells, and is considered as one of the main stemness markers. It also has pivotal roles in early stages of ...embryonic development. Most studies on OCT4 have focused on the expression and function of OCT4A, which is the biggest isoform of OCT4 known so far. Recently, many studies have shown that OCT4 has various transcript variants, protein isoforms, as well as pseudogenes. Distinguishing the expression and function of these variants and isoforms is a big challenge in expression profiling studies of OCT4. Understanding how OCT4 is functioning in different contexts, depends on knowing of where and when each of OCT4 transcripts, isoforms and pseudogenes are expressed. Here, we review OCT4 known transcripts, isoforms and pseudogenes, as well as its interactions with other proteins, and emphasize the importance of discriminating each of them in order to understand the exact function of OCT4 in stem cells, normal development and development of diseases.
Alternative promoter and alternative splicing are two important mechanisms of gene regulation and protein diversity in different physiological contexts of eukaryotes, especially in stem cells and ...developmental stages. Pou5f1 gene which codes the stemness marker OCT4, utilizes alternative splicing and promoter mechanisms, which result in generation of multiple spliced variants and subsequently multiple protein isoforms. By far, nine variants of OCT4 (OCT4A, OCT4B, OCT4B1, OCT4B2, OCT4B3, OCT4B4, OCT4C, OCT4C1, and OCT4D) have been introduced. It has been well established that OCT4A plays essential roles in early developmental stages as well as maintenance of stemness in embryonic stem cells (ESCs). However, the roles and functions of other variants and isoforms of OCT4 in biological systems are less appreciated. In this study, we report a new OCT4 variant, designated as OCT4B5. RT-PCR assay on different human cell lines including pluripotent, normal and cancer cells showed that OCT4B5 is expressed at variable level in different cell lines. By semi-quantifying of OCT4B5 expression in pluripotent and differentiated states of NT2 cell lines, we reveal that this variant of OCT4 is highly expressed in undifferentiated state and its expression is down-regulated upon differentiation. Compared to OCT4A which is sharply down-regulated in retinoic acid induced differentiation of NT2 cell line, the expression of OCT4B5 remains at low level in differentiated state. Overall, this study emphasizes the complexity of OCT4 gene expression and regulation in different states of stem cells and physiological contexts. Graphical Abstract.
OCT4 is a crucial transcription factor that maintains self-renewal and pluripotency of embryonic stem and embryonic carcinoma cells. The human OCT4 gene can generate at least three variants (OCT4A, ...OCT4B, and OCTB1) via alternative splicing and alternative promoters. It has been previously reported that OCT4A is the main isoform, retaining stemness state in embryonic stem and embryonic carcinoma cells. There are several reports on the expression of OCT4A, OCT4B, and OCT4B1 in some cancers and tumor cells. The expression of OCT4 in cancer tissues and cell lines appeared to be highly controversial since it was believed that OCT4 is exclusively expressed in embryonic stem/embryonic carcinoma cells. Here, we are reporting the detection of a novel alternatively spliced variant of OCT4, OCT4B2, in several pluripotent and tumor cell lines. Moreover, the expression pattern of OCT4B2 in the course of neural differentiation of NT2 and NCCIT, embryonic carcinoma cells, was similar to that of OCT4A. OCT4B2 was highly expressed in undifferentiated cells; however, its expression was sharply downregulated upon induction of differentiation. Overexpression of OCT4B2 did not affect the distribution of cells in different cell-cycle phases of transfected cells, compared to the mock transfected cells. Interestingly, the expression of OCT4B2 transcript was elevated under the heat-shock induction. In conclusion, we are reporting a new variant of OCT4, which is expressed under different physiological conditions. The finding shed more light on complexity of OCT4 expression and functions.
N6-methyladenosine (m6A) is the most abundant modification to mRNAs. Loss-of-function studies of main m6A regulators have indicated the role of m6A in pre-mRNA splicing. Recent studies have reported ...the role of splicing in preventing m6A deposition. Understanding the interplay between m6A and mRNA splicing holds the potential to clarify the significance of these fundamental molecular mechanisms in cell development and function, thereby shedding light on their involvement in the pathogenesis of myriad diseases.
•m6A RNA modification and mRNA splicing have been reported to regulate each other.•Splice site m6A has been shown to regulate splicing via specific m6A reader proteins.•Splicing inhibits m6A deposition in short exons.•Profiling m6A on nascent mRNAs may reveal a broader role of m6A in splicing regulation.
Sortilin (also known as neurotensin receptor 3) is a multitasking protein implicated in numerous pathophysiological processes, including cancer development, cardiovascular impairment, Alzheimer‐type ...dementia, and depression. Although the definitive role of sortilin in human solid and hematological malignancies has been evidenced, few articles reviewed the task. The aim of the current review is to unravel the mechanisms by which sortilin controls oncogenicity and cancer progression; and also to summarize and discuss the original data obtained from international research laboratories on this topic. Questions on how sortilin is involving in the impairment of cell junctions, in exosomes composition and release, as well as in the regulation of epidermal growth factor receptor trafficking are also responded. In addition, we provide a special focus on the regulatory role of sortilin in signal transduction by either neurotrophins or neurotensin in normal and malignant cells. The relevance of sortilin with normal and cancer stem cells is also discussed. The last section provides a general overview of sortilin applications as a diagnostic and prognostic biomarker in the context of cancer detection. Finally, we comment on the future research aspects in which the field of cancer diagnosis, prognosis, and therapy might be developed.
Sortilin (neurotensin receptor 3) is a multitasking protein implicated in numerous pathophysiological processes, including cancer development, cardiovascular impairment, Alzheimer‐type dementia, and depression. In this study, we discuss the mechanisms by which sortilin is involved in pathophysiological conditions with the main focus on cancer. We also comment on the future research aspects in which the field of cancer diagnosis, prognosis, and therapy might be developed.
Cover Image, Volume 236, Number 9, September 2021 Ghaemimanesh, Fatemeh; Mehravar, Majid; Milani, Saeideh ...
Journal of cellular physiology,
September 2021, 2021-09-00, Letnik:
236, Številka:
9
Journal Article
Recenzirano
Front Cover: The cover image is based on the Review Article The Multifaceted Role of Sortilin/Neurotensin Receptor 3 in Human Cancer Development by Fatemeh Ghaemimanesh et al., ...https://doi.org/10.1002/jcp.30344.
Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is a multifunctional protein expressed in diverse normal tissues, and functionally is involved in cellular matrix and signaling ...processes. Many studies have linked SPP1 to pathophysiological conditions including cancer.
The aim of this study is to evaluate the 3'UTR length of SPP1 gene in glioblastoma cell line.
3' Rapid Amplification of cDNA End (3'-RACE) were used to determine the 3' end of SPP1 gene. APAatlas data base, GEPIA web server, and miRcode were also used to extract related information and bioinformatic analysis part.
In this study we show that SPP1 gene undergoes Alternative cleavage and Polyadenylation (APA) mechanism, by which it generates two 3' termini, longer isoform and shorter isoform, in glioblastoma derived cell line, U87-MG. Further bioinformatic analysis reveals that SPP1 alternative 3'UTR (aUTR), which is absent in shorter isoform, is targeted by two families of microRNAs-miR-181abcd/4262 and miR-154/872. These miRNAs also target and perhaps negatively regulate NAP1L1 and ENAH genes that are involved in cell proliferation and cell polarity, respectively. Relative expression difference (RED), obtained from RNA-seq data of diverse normal tissues, representing APA usage appears to be negatively correlated with expression of NAP1L1 and ENAH, emphasizing co-expression of SPP1 longer isoform with these two genes, indicating miRNA sponge function of aUTR (longer 3'UTR). Bioinformatic analysis also shows that in normal brain tissue longer APA isoform of SPP1 is expressed; however shorter isoform appears to be expressed in cancer condition.
Together, this study reveals that SPP1 APA isoforms have different pattern in normal and cancerous conditions, which can be considered as a diagnostic and prognostic marker in cancers.
POU domain proteins are an important family of transcription factors that regulates cell type-specific gene expression. One of the most crucial members of this family that maintains pluripotency and ...self-renewal of embryonic stem cells is POU5F1/OCT4. The OCT4 gene can generate several variants under different situations/cell types includes OCT4A that is the major factor sustains pluripotency in embryonic stem and embryonic carcinoma cells, and also OCT4B and OCT4B1, which are transcribed from a different potential promoter located in intron1 and are expressed in various tissues and cell types.
In present study, during expression check of OCT4B1 in embryonic carcinoma cells (NT2), we discovered a novel OCT4 transcript for the first time and designated it as OCT4B4. This variant is expressed in various human pluripotent cells and its expression is down-regulated upon induction of differentiation. Moreover, knocking down of OCT4B4 by shRNA resulted in increased accumulation of transfected cells in G0/G1 phase compared to the mock-transfected control cells.
•OCT4 generates several variants, mostly via alternative splicing.•The novel OCT4B4 variant is primarily expressed in undifferentiated cells and down regulated upon induction of differentiation.•OCT4B4 expression was detected only in pluripotent cells among several human cell lines.•OCT4B4 suppression induced significant changes in cell cycle distribution, mostly in G0/G1 and G2/M phases.
PDF
