Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Tam, Oliver H.; Ostrow, Lyle W.; Hammell, Molly

doi:10.1186/s13100-019-0176-1

Cited by 97 publications

(95 citation statements)

References 153 publications

(215 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the innate LTR expression within dnmt1 +/+ RSCs, in conjunction with previous reports of inherent RE activity within human neural tissue, it is worth considering how RE activity may contribute to neural stem cell biology. It is well known that dysregulation of REs is a hallmark of many human neurodegenerative diseases 67,[79][80][81][82] . Future evaluations regarding the innate cost-to-benefit ratio of RE activity could provide crucial evidence for the development of neurodegenerative therapies.…”

Section: Discussionmentioning

confidence: 99%

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

View full text Add to dashboard Cite

The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase, dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafish dnmt1 s872 mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry, in situ hybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in the dnmt1 -/-CMZ, but in a p53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in the dnmt1 -/-CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye. Introduction:The distal region of the vertebrate retina, termed the ciliary marginal zone (CMZ), contains a population of resident retinal stem cells (RSCs). The CMZ remains proliferative throughout the life of fish, but it proliferates to a more limited extent during the lifetime of amphibians and birds 1-6 . Whether an analogous structure exists in mammals is debated, but there are distinct, progenitor-like cells in the periphery of the retina that are active during embryogenesis 7-9 . Mammalian RSCs can also be isolated from the adult ciliary margin, cultured in vitro, and stimulated to produce retinal neurons 10-13 .However, this activity has not been demonstrated in the mature mammalian retinae in vivo.Studies of the CMZ have primarily focused on zebrafish and Xenopus models to determine genetic pathways required for RSC identity 2,14-16 and to characterize the epigenetic networks which regulate RSC function 17,18 . By comparison, the mechanisms mediating RSC maintenance in vivo remain unknown. In studies of RSCs, the zebrafish has been advantageous given that it possesses a highly active RSC population and is tractable for genetic and pharmacological manipulations, transgenesis and in vivo imaging 19,20 .DNA methylation, a frequently studied epigenetic modification, is the process through which a methyl group is added to the fifth carbon of cytosine nucleotides and is commonly found at CpG dinucleotide sequences 21 . Members of the family of DNA methyltransferase (Dnmt) enzymes 22,23 catalyze this epigenetic modification. Dnmt1 serves as a maintenance methyltransferase, copying the methylation pattern from parent to daughter strand during DNA replication and its function is required for cell cycle progression [24][25][26] . Loss of Dnmt1 function results in genomic hypomethylation 27-29 and in developmental contexts and specific organ systems, this often compromises progenitor cell maintenance 24...

show abstract

Section: Discussionmentioning

confidence: 99%

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

Angileri

Gross

2020

Preprint

View full text Add to dashboard Cite

show abstract

“… Abstract Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that impact genome regulation and cell physiology throughout their RNA-centered life cycle 1 . Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases 2–4 . Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m 6 A RNA methylation as a novel means of ERV restriction.…”

mentioning

confidence: 99%

m⁶A RNA methylation regulates the fate of endogenous retroviruses

Chelmicki

Roger

Teissandier

et al. 2020

Preprint

View full text Add to dashboard Cite

27 28 29 Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated 30 retroviral sequences that impact genome regulation and cell physiology throughout 31 their RNA-centered life cycle 1 . Failure to repress ERVs is associated with cancer, 32 infertility, senescence and neurodegenerative diseases 2-4 . Here, using an unbiased 33 genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify 34 m 6 A RNA methylation as a novel means of ERV restriction. Methylation of ERV mRNAs 35 is catalyzed by the complex of methyltransferase-like METTL3/METTL14 5 proteins 36 whose depletion, along with their accessory subunits, WTAP and ZC3H13, led to 37 increased mRNA abundance of Intracisternal A-particles (IAPs) and related ERVK 38 elements specifically, by targeting their 5'UTR region. Using controlled auxin-39 dependent degradation of the METTL3/METTL14 enzymatic complex, we showed that 40 IAP mRNA and protein abundance is dynamically and inversely correlated with m 6 A 41 catalysis. By monitoring mRNA degradation rates upon METTL3/14 double degron, we 42 further proved that m 6 A methylation destabilizes IAP transcripts. Finally, similarly to 43 m 6 A writers, triple knockout of the m 6 A readers YTHDF1, DF2 and DF3 6 increased IAP 44 mRNA abundance. This study sheds light onto a novel function of RNA methylation in 45 protecting cellular integrity by clearing reactive ERV-derived RNA species, which may 46 be especially important when transcriptional silencing is less stringent.repressors, by transducing cells with single guide (sg)RNAs against the KRAB-associated 80 protein 1 (KAP1) 11 (Extended Data Fig. 1d,e, Supplementary Fig. 1, Supplementary Table 2, 81 Supplementary Table 3). 4For the screen, we transduced IAPEz-reporter cells with a lentiviral genome-wide 83 sgRNA library at multiplicity of infection (MOI)= 0.2-0.3 12 (Fig. 1b). Frequencies of sgRNAs 84 upon blasticidin selection (5, 7 and 9 days) versus non-selected conditions were assessed 85 via deep sequencing and candidate genes were identified using Model-based Analysis of 86 Genome-wide CRISPR/Cas9 Knockout (MAGeCK) 13 . Efficiency of selection was evidenced 87 by drop-out of control intergenic sgRNAs and genes were ranked based on sgRNA P-values 88 ( Fig. 1c, Supplementary Table 4, Supplementary Table 5). Although genome-wide screens of 89 this magnitude typically suffer from low-statistical confidence, we identified several-but not 90 all-genes previously associated with ERV repression (Resf1, Trp53, Daxx, Atrx, Uhrf1, 91 Cbx1, Dnmt1) 14-17 among the top 100 hits. Obtaining an incomplete list of known regulators 92 is a common outcome of genome-wide screens which can be due to multiple factors 93 including time-dependent dropout of essential genes with strong effects on cell viability (such 94 as Kap1) 18 , heterogeneity in sgRNA efficiencies or limited representation of sgRNAs. 95Nonetheless, we were able to identify several novel candidates for IAP control 96( Supplementary Table 4), offering a foundation for futu...

show abstract

“…Outside the germline, TE overexpression is described in several neurodegenerative disorders, including ALS and Alzheimer's Disease (reviewed in ref. [46]). In this case, existing evidence points to the transcription of TE‐derived RNAs as responsible for pathology.…”

Section: The Connection Between Derepression Of Tes and Diseasementioning

confidence: 99%

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

2020

View full text Add to dashboard Cite

Transposable elements (TEs) are sequences currently or historically mobile, and are present across all eukaryotic genomes. A growing interest in understanding the regulation and function of TEs has revealed seemingly dichotomous roles for these elements in evolution, development, and disease. On the one hand, many gene regulatory networks owe their organization to the spread of cis‐elements and DNA binding sites through TE mobilization during evolution. On the other hand, the uncontrolled activity of transposons can generate mutations and contribute to disease, including cancer, while their increased expression may also trigger immune pathways that result in inflammation or senescence. Interestingly, TEs have recently been found to have novel essential functions during mammalian development. Here, the function and regulation of TEs are discussed, with a focus on LINE1 in mammals. It is proposed that LINE1 is a beneficial endogenous dual regulator of gene expression and genomic diversity during mammalian development, and that both of these functions may be detrimental if deregulated in disease contexts.

show abstract

Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Cited by 97 publications

References 153 publications

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

m⁶A RNA methylation regulates the fate of endogenous retroviruses

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

Contact Info

Product

Resources

About

Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Cited by 97 publications

References 153 publications

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

m6A RNA methylation regulates the fate of endogenous retroviruses

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

Contact Info

Product

Resources

About

m⁶A RNA methylation regulates the fate of endogenous retroviruses