Transcriptome instability

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Transcriptome instability is a genome-wide, pre-mRNA splicing-related characteristic of certain cancers. In general, pre-mRNA splicing is dysregulated in a high proportion of cancerous cells. [1] [2] [3] For certain types of cancer, like in colorectal and prostate, the number of splicing errors per cancer has been shown to vary greatly between individual cancers, a phenomenon referred to as transcriptome instability. [4] [5] Transcriptome instability correlates significantly with reduced expression level of splicing factor genes. Mutation of DNMT3A contributes to development of hematologic malignancies, and DNMT3A -mutated cell lines exhibit transcriptome instability as compared to their isogenic wildtype counterparts. [6]

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Transcription (biology) Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). Averaged over multiple cell types in a given tissue, the quantity of mRNA is more than 10 times the quantity of ncRNA. The general preponderance of mRNA in cells is valid even though less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

Alternative splicing Process by which a single gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions. Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

Regulation of gene expression Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

The transcriptome is the set of all RNA transcripts, including coding and non-coding, in an individual or a population of cells. The term can also sometimes be used to refer to all RNAs, or just mRNA, depending on the particular experiment. The term transcriptome is a portmanteau of the words transcript and genome; it is associated with the process of transcript production during the biological process of transcription.

Rapid amplification of cDNA ends (RACE) is a technique used in molecular biology to obtain the full length sequence of an RNA transcript found within a cell. RACE results in the production of a cDNA copy of the RNA sequence of interest, produced through reverse transcription, followed by PCR amplification of the cDNA copies. The amplified cDNA copies are then sequenced and, if long enough, should map to a unique genomic region. RACE is commonly followed up by cloning before sequencing of what was originally individual RNA molecules. A more high-throughput alternative which is useful for identification of novel transcript structures, is to sequence the RACE-products by next generation sequencing technologies.

Fusion gene

A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neoplasia. The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.

Oncogenomics Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

HMGA2 Protein-coding gene in the species Homo sapiens

High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.

DNA (cytosine-5)-methyltransferase 3A

DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.

NKX3-1

Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p. NKX3-1 is a prostatic tumor suppressor gene.

PTPRT

Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.

RNA-Seq Lab technique in cellular biology

RNA-Seq is a sequencing technique which uses next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample at a given moment, analyzing the continuously changing cellular transcriptome.

Cancer genome sequencing is the whole genome sequencing of a single, homogeneous or heterogeneous group of cancer cells. It is a biochemical laboratory method for the characterization and identification of the DNA or RNA sequences of cancer cell(s).

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

In molecular biology, mir-720 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

DNA methylation in cancer plays a variety of roles, helping to change the healthy regulation of gene expression to a disease pattern.

IRF2BP2 (gene)

Interferon regulatory factor 2 binding protein 2 is a protein that in humans is encoded by the IRF2BP2 gene.

Transcriptomics technologies are the techniques used to study an organism's transcriptome, the sum of all of its RNA transcripts. The information content of an organism is recorded in the DNA of its genome and expressed through transcription. Here, mRNA serves as a transient intermediary molecule in the information network, whilst non-coding RNAs perform additional diverse functions. A transcriptome captures a snapshot in time of the total transcripts present in a cell. Transcriptomics technologies provide a broad account of which cellular processes are active and which are dormant. A major challenge in molecular biology lies in understanding how the same genome can give rise to different cell types and how gene expression is regulated.

References

  1. Skotheim, R I; Nees, M (2007). "Alternative splicing in cancer: noise, functional, or systematic?". The International Journal of Biochemistry & Cell Biology. 39 (7–8): 1432–49. doi:10.1016/j.biocel.2007.02.016. PMID   17416541.
  2. Bauer, Joseph Alan; He, Chunjiang; Zhou, Fang; Zuo, Zhixiang; Cheng, Hanhua; Zhou, Rongjia (2009). Bauer, Joseph Alan (ed.). "A Global View of Cancer-Specific Transcript Variants by Subtractive Transcriptome-Wide Analysis". PLOS ONE. 4 (3): e4732. Bibcode:2009PLoSO...4.4732H. doi: 10.1371/journal.pone.0004732 . PMC   2648985 . PMID   19266097.
  3. Sveen, A; Kilpinen, S; Ruusulehto, A; Lothe, RA; Skotheim, RI (2015). "Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes". Oncogene. 35 (19): 2413–2427. doi: 10.1038/onc.2015.318 . PMID   26300000.
  4. Sveen, A; Ågesen, TH; Nesbakken, A; Rognum, TO; Lothe, RA; Skotheim, RI (2011). "Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival". Genome Medicine. 15: 672. doi:10.1186/1471-2164-15-672. PMC   3219073 . PMID   25109687.
  5. Sveen, A; Johannessen, B; Teixeira, MR; Lothe, RA; Skotheim, RI (2014). "Transcriptome instability as a molecular pan-cancer characteristic of carcinomas". BMC Genomics. 3 (5): 32. doi:10.1186/gm248. PMC   4137096 . PMID   21619627.
  6. Banaszak, LG; Giudice, V; Zhao, X; Wu, Z; Gao, S; Hosokawa, K; Keyvanfar, K; Townsley, DM; Gutierrez-Rodrigues, F; Ibanez, MdPF; Kajigaya, S; Young, NS (2018). "Abnormal RNA splicing and genomic instability after induction of DNMT3A mutations by CRISPR/Cas9 gene editing". Blood Cells, Molecules and Diseases. 69: 10–22. doi:10.1016/j.bcmd.2017.12.002. PMC   6728079 . PMID   29324392.