The Intersection of Genetics and Epigenetics: Reactivation of Mammalian LINE-1 Retrotransposons by Environmental Injury

Ramos, Kenneth S.; Teneng, Ivo; Montoya-Durango, Diego E.; Bojang, Pasano; Haeberle, M Tye; Ramos, Irma N.; Stribinskis, Vilius; Kalbfleisch, Ted

doi:10.1007/978-3-642-23380-7_6

Cited by 7 publications

(8 citation statements)

References 206 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20–22 Most L1 insertions are truncated at the 5′ end and carry sequence changes that render newly inserted elements unable to retrotranspose. 23 Genome-wide analysis has identified ∼100 human and 3000 mouse retrotransposition competent, full-length L1s. 24–26 These sequences have been compiled and are available at…”

Section: L1 Architecture Expression and Functionmentioning

confidence: 99%

Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Ramos

Bojang

Bowers

2021

Exp Biol Med (Maywood)

Self Cite

View full text Add to dashboard Cite

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.

show abstract

Section: L1 Architecture Expression and Functionmentioning

confidence: 99%

Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Ramos

Bojang

Bowers

2021

Exp Biol Med (Maywood)

Self Cite

View full text Add to dashboard Cite

show abstract

“…30 These repressive marks can be removed by aberrant endogenous cellular processes and/or exposure to agents that induce DNA damage or perturb the epigenome. 31 Reactivation of LINE-1 can reprogram the genome by causing insertion mutations or deletions that disrupt genome architecture and function. [32][33][34] Additionally, LINE-1 activation can initiate aberrant gene expression changes that are independent of retrotransposition.…”

Section: Long Interspersed Nuclear Element-1 As a Therapeutic Targetmentioning

confidence: 99%

Precision prevention: A focused response to shifting paradigms in healthcare

Ramos

Bowers

Tavera-Garcia

et al. 2019

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Human health and disease are defined at the intersection of molecules, environment, and lifestyle, which combined determine phenotypic outcomes. To date, most clinical applications in the precision medicine space have focused on DNA, with lesser attention given to the biology encoded by RNA molecules, or the complexity of biological regulation at the level of proteins and metabolites. The totality of this information must be integrated in ways that allow for implementation of knowledge-based health promotion and prevention strategies that can help address current limitations in healthcare delivery. This review describes recent advances in the development of diagnostic tools for early detection and stratification of individuals suffering from chronic obstructive pulmonary disease and their heightened risk for the development of lung malignancies. Impact statement The study of LINE-1 retroelements and their role in the pathogenesis of diseases of the lung such as COPD and lung cancer may provide valuable diagnostic and therapeutic tools to identify pre-emptively individuals at risk of pulmonary disease progression. Limited information is presently available on the role of LINE-1 in the regulation of disease phenotypes and the development of novel therapeutics designed to curtail LINE-1-mediated pathogenesis. Successful implementation of precision prevention strategies may help to spare those impacted by obstructive pulmonary disease from continued deterioration, while realizing significant cost savings and improved quality of healthcare.

show abstract

“…Human L1s are non-LTR mammalian retrotransposons that consist of an internal bidirectional promoter, two open reading frames encoding for ORF1p (RNA-binding protein) and ORF2p (reverse transcriptase and endonuclease activities), a 3′- untranslated region (UTR), and a polyA tail [ 1 ]. Murine L1s share similar structural and functional features, except that the 5′-UTR is organized into monomeric units that function as an upstream promoter [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…While L1s are highly active during early embryonic development, they are targeted for epigenetic silencing via DNA methylation and histone covalent modifications during the course of differentiation [ 3 ]. L1 reactivation is strongly associated with the acquisition of oncogenic phenotypes resulting from insertion mutagenesis and/or reprogramming of gene expression [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex

et al. 2016

Self Cite

View full text Add to dashboard Cite

BackgroundLong Interspersed Nuclear Element-1 (L1) is an oncogenic mammalian retroelement silenced early in development via tightly controlled epigenetic mechanisms. We have previously shown that the regulatory region of human and murine L1s interact with retinoblastoma (RB) proteins to effect retroelement silencing. The present studies were conducted to identify the corepressor complex responsible for RB-mediated silencing of L1.MethodsChromatin immunoprecipitation and silencing RNA technology were used to identify the repressor complex that silences L1 in human and murine cells.ResultsComponents of the Nucleosomal and Remodeling Deacetylase (NuRD) multiprotein complex specifically enriched the L1 5′-untranslated DNA sequence in human and murine cells. Genetic ablation of RB proteins in murine cells destabilized interactions within the NuRD macromolecular complex and mediated nuclear rearrangement of Mi2-β, an ATP-dependent helicase subunit with nucleosome remodeling activity. Depletion of Mi2-β, RbAP46 and HDAC2 reduced the repressor activity of the NuRD complex and reactivated a synthetic L1 reporter in human cells. Epigenetic reactivation of L1 in RB-null cells by DNA damage was markedly enhanced compared to wild type cells.ConclusionsRB proteins stabilize interactions of the NuRD corepressor complex within the L1 promoter to effect L1 silencing. L1 retroelements may serve as a scaffold on which RB builds heterochromatic regions that regulate chromatin function.

show abstract

The Intersection of Genetics and Epigenetics: Reactivation of Mammalian LINE-1 Retrotransposons by Environmental Injury

Cited by 7 publications

References 206 publications

Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Precision prevention: A focused response to shifting paradigms in healthcare

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex

Contact Info

Product

Resources

About