LINE1
LINE1 (also L1 and LINE-1) is a family of related class I
L1 gene products are also required by many non-autonomous Alu and SVA SINE retrotransposons. Mutations induced by L1 and its non-autonomous counterparts have been found to cause a variety of heritable and somatic diseases.[4][5]
In 2011, human L1 was reportedly discovered in the genome of the gonorrhea bacteria, evidently having arrived there by horizontal gene transfer.[6][7]
Structure
A typical L1 element is approximately 6,000 base pairs (bp) long and consists of two non-overlapping open reading frames (ORFs) which are flanked by untranslated regions (UTRs) and target site duplications. In humans, ORF2 is thought to be translated by an unconventional termination/reinitiation mechanism,[8] while mouse L1s contain an internal ribosome entry site (IRES) upstream of each ORF.[9]
5' UTR
The 5' UTRs of mouse L1s contain a variable number of GC-rich
ORF1
| LINE-1 (L1.2) retrotransposable element ORF1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | L1RE1 | ||||||
| Alt. symbols | L1ORF1p | ||||||
Chr. 22 q12.1 | |||||||
| Wikidata | Q18028646 | ||||||
| |||||||
The first
ORF2
| LINE-1 retrotransposable element ORF2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | L1RE2 | ||||||
| Alt. symbols | L1ORF2p | ||||||
Chr. 1 q | |||||||
| Wikidata | Q18028649 | ||||||
| |||||||
The second
The
Regulation
As with other transposable elements, the host organism keeps a heavy check on LINE1 to prevent it from becoming overly active. In the primitive eukaryote Entamoeba histolytica, ORF2 is massively expressed in antisense, resulting in no detectable amounts of its protein product.[16]
Roles in disease
Cancer
L1 activity has been observed in numerous types of cancers, with particularly extensive insertions found in colorectal and lung cancers.[17] It is currently unclear if these insertions are causes or secondary effects of cancer progression. However, at least two cases have found somatic L1 insertions causative of cancer by disrupting the coding sequences of genes APC and PTEN in colon and endometrial cancer, respectively.[2]
Quantification of L1 copy number by qPCR or L1 methylation levels with bisulfite sequencing are used as diagnostic biomarkers in some types of cancers. L1 hypomethylation of colon tumor samples is correlated with cancer stage progression.[18][19] Furthermore, less invasive blood assays for L1 copy number or methylation levels are indicative of breast or bladder cancer progression and may serve as methods for early detection.[20][21]
Neuropsychiatric disorders
Higher L1 copy numbers have been observed in the human brain compared to other organs.[22][23] Studies of animal models and human cell lines have shown that L1s become active in neural progenitor cells (NPCs), and that experimental deregulation of or overexpression of L1 increases somatic mosaicism. This phenomenon is negatively regulated by Sox2, which is downregulated in NPCs, and by MeCP2 and methylation of the L1 5' UTR.[24] Human cell lines modeling the neurological disorder Rett syndrome, which carry MeCP2 mutations, exhibit increased L1 transposition, suggesting a link between L1 activity and neurological disorders.[25][24] Current studies are aimed at investigating the potential roles of L1 activity in various neuropsychiatric disorders including schizophrenia, autism spectrum disorders, epilepsy, bipolar disorder, Tourette syndrome, and drug addiction.[26] L1s are also highly expressed in octopus brain, suggesting a convergent mechanism in complex cognition.[27]
Retinal disease
Increased RNA levels of Alu, which requires L1 proteins, are associated with a form of age-related macular degeneration, a neurological disorder of the eyes.[28]
The naturally occurring mouse retinal degeneration model rd7 is caused by an L1 insertion in the Nr2e3 gene.[29]
Assistance to telomere reprogramming
It has been suggested that L1s may directly contribute to telomere reprogramming at the 2-cell stage of embryo development.[30][31]
COVID-19
In 2021, a study proposed that L1 elements may be responsible for potential endogenisation of the SARS-CoV-2 genome in Huh7 mutant cancer cells,[32] which would possibly explain why some patients test PCR positive for SARS-CoV-2 even after clearance of the virus. These results however have been criticized as not reproducible,[33] misleading and infrequent[34] or artefactual.[35]
See also
References
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- ^ Yong E (2011-02-16). "Gonorrhea has picked up human DNA (and that's just the beginning)". National Geographic. Archived from the original on December 5, 2019. Retrieved 2016-07-14.
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- ^ Wang, F., Chamani, I.J., Luo, D. et al. (2021). Inhibition of LINE-1 retrotransposition represses telomere reprogramming during mouse 2-cell embryo development. J Assist Reprod Genet https://doi.org/10.1007/s10815-021-02331-w
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Further reading
- Tan K, Kim ME, Song HW, Skarbrevik D, Babajanian E, Bedrosian TA, et al. (June 2021). "The Rhox gene cluster suppresses germline LINE1 transposition". Proceedings of the National Academy of Sciences of the United States of America. 118 (23): e2024785118. PMID 34083437.
- Tan K, Song HW, Wilkinson MF (July 2021). "RHOX10 drives mouse spermatogonial stem cell establishment through a transcription factor signaling cascade". Cell Reports. 36 (3): 109423. PMID 34289349.
- Protasova MS, Andreeva TV, Rogaev EI (September 2021). "Factors Regulating the Activity of LINE1 Retrotransposons". Genes. 12 (10): 1562. PMID 34680956.
- Zheng F, Kawabe Y, Murakami M, Takahashi M, Nishihata K, Yoshida S, et al. (July 2021). "LINE-1 vectors mediate recombinant antibody gene transfer by retrotransposition in Chinese hamster ovary cells". Biotechnology Journal. 16 (7): e2000620. S2CID 233484152.
- Jachowicz JW, Bing X, Pontabry J, Bošković A, Rando OJ, Torres-Padilla ME (October 2017). "LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo". Nature Genetics. 49 (10): 1502–1510. S2CID 5213902.
- Wehbi SS, Zu Dohna H (November 2021). "A comparative analysis of L1 retrotransposition activities in human genomes suggests an ongoing increase in L1 number despite an evolutionary trend towards lower activity". Mobile DNA. 12 (1): 26. PMID 34782009.
- Garcia-Perez JL, Marchetto MC, Muotri AR, Coufal NG, Gage FH, O'Shea KS, Moran JV (July 2007). "LINE-1 retrotransposition in human embryonic stem cells". Human Molecular Genetics. 16 (13): 1569–1577. PMID 17468180.
- Lu JY, Chang L, Li T, Wang T, Yin Y, Zhan G, et al. (June 2021). "Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome". Cell Research. 31 (6): 613–630. PMID 33514913.