User:Czelinka/sandbox

LINE1 roles

- diseases: cancer, autism, schizophrenia, epilepsy, drug addiction

- ageing

- mosaicism: germline, neural progenitors

- genome stability

- regulated by: sirt6, sox2, MeCP2, siRNA, methylation, melatonin

- regulates: ASARs, SINEs, genome stability (through melatonin)

- misc: L1 insertion in rd7 mouse

Clinical significance/roles in disease

L1s are commonly expressed in the germline and developing embryo, where insertions contribute to genomic variation. However, somatic L1 activity is implicated in cancer and neuropsychiatric disorders.

L1s are commonly expressed in germ cells and during early embryogenesis, where insertions contribute to genomic variation in humans. More recent evidence suggests that L1s are also expressed in neural progenitor cells (NPCs) in flies, rodents, and humans. This activity has been proposed as a mechanism to drive neuronal complexity (Muotri et al., 2006), however aberrant insertions are currently being investigated as potential causes for various neuropsychiatric disorders such as Rett Syndrome, schizophrenia, autism spectrum disorders, Tourette Syndrome, epilepsy, bipolar disorder, and drug addiction.

L1s are commonly expressed in germ cells and the developing embryo, where insertions contribute to genomic variation. More recent evidence suggests that L1s can also be expressed in neural progenitor cells (NPCs) and may, at least in part, contribute to somatic cell mosaicism of the brain. This activity is a proposed mechanism that drives neuronal variation and complexity.

Aberrant L1 activity is implicated in a number of cancers, including breast, colon, testicular and bladder cancer.

overexpression of line1?

= LINE1 = From Wikipedia, the free encyclopedia

LINE1 (also L1 and LINE-1) are class I transposable elements in the DNA of some organisms and belong to the group of Long interspersed nuclear elements (LINEs). L1 comprise approximately 17% of the human genome. The majority of L1 in the human genome are inactive; however, about 80-100 copies have retained the ability to retrotranspose, with considerable variation between individuals. These active L1s can interrupt the genome through insertions, deletions, rearrangements, and copy number variations (CNV). L1 activity has contributed to the instability and evolution of genomes, and is tightly regulated in the germline by DNA methylation, histone modifications, and piRNA. L1s can further impact genome variation by mispairing and unequal crossing-over during meiosis due to its repetitive DNA sequences.

L1 gene products are also required by many nonautonomous Alu and SVA retrotransposons. Mutations induced by L1 and its nonautonomous counterparts have been found to cause a variety of heritable and somatic diseases.

Human L1 has been reported to have transferred to the genome of the gonorrhea bacteria.

Regulation

binding sites for sox2, yy1, runx3, tcf, lef, etc (erwin 2014)

mecp2 and methylation

Roles in disease

Cancer

L1 activity has been observed in numerous types of cancers, with particularly extensive insertions found in colorectal and lung cancers. It is currently unclear if these insertions are causal 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 cancers, respectively.

Quantification of L1 copy number or L1 methylation levels are used as diagnostic biomarkers in some types of cancers. L1 hypomethylation of colon tumor samples is correlated with cancer stage progression. 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.

Neuropsychiatric disorders

Higher L1 copy numbers have been observed in the human brain compared to other organs. 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. 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. 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.

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. (kaz 2017 or kaneko 2011)

The naturally occurring mouse retinal degeneration model rd7 is caused by an L1 insertion in the Nr2e3 gene. (chen 2006)