Transposable element sequence fragments incorporated into coding and noncoding transcripts modulate the transcriptome of human pluripotent stem cells DOI Creative Commons
Isaac A. Babarinde, Gang Ma, Yuhao Li

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(16), P. 9132 - 9153

Published: Aug. 3, 2021

Transposable elements (TEs) occupy nearly 40% of mammalian genomes and, whilst most are fragmentary and no longer capable transposition, they can nevertheless contribute to cell function. TEs within genes transcribed by RNA polymerase II be copied as parts primary transcripts; however, their full contribution mature transcript sequences remains unresolved. Here, using long short read (LR SR) sequencing data, we show that 26% coding 65% noncoding transcripts in human pluripotent stem cells (hPSCs) contain TE-derived sequences. Different TE families incorporated into RNAs unique patterns, with consequences structure The presence a is correlated TE-type specific changes its subcellular distribution, alterations steady-state levels half-life, differential association Binding Proteins (RBPs). We identify hPSC-specific incorporation endogenous retroviruses (ERVs) LINE:L1 protein-coding mRNAs, which generate sequence-derived peptides. Finally, single RNA-seq reveals hPSCs express ERV-containing transcripts, differentiating subpopulations lack ERVs SINE LINE-containing transcripts. Overall, our comprehensive analysis demonstrates the more widespread has greater impact than previously appreciated.

Language: Английский

FTO mediates LINE1 m 6 A demethylation and chromatin regulation in mESCs and mouse development DOI
Jiangbo Wei, Xianbin Yu, Lei Yang

et al.

Science, Journal Year: 2022, Volume and Issue: 376(6596), P. 968 - 973

Published: May 5, 2022

-methyladenosine (m

Language: Английский

Citations

170
Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome DOI Creative Commons
Jiangbo Lu, Lei Chang, Tong Li

et al.

Cell Research, Journal Year: 2021, Volume and Issue: 31(6), P. 613 - 630

Published: Jan. 29, 2021

Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved relatively stable during lineage differentiation. In an effort unravel basic principle underlying folding, here we focus on itself report a fundamental role for L1 (LINE1 or LINE-1) B1/Alu retrotransposons, most abundant subclasses repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering demarcates grossly exclusive domains, characterizes predicts Hi-C compartments. Spatial segregation L1-rich sequences nuclear nucleolar peripheries B1/Alu-rich interior is mouse human cells occurs dynamically cell cycle. addition, de novo establishment B1 coincident with formation higher-order structures early embryogenesis critically regulated by transcripts. Importantly, depletion transcripts embryonic stem drastically weakens repeat contacts compartmental strength, disrupts L1- B1-rich chromosomal at genome-wide individual sites. Mechanistically, co-localization liquid droplet DNA RNA protein HP1α suggest phase-separation mechanism which promotes Taken together, propose genetically encoded model repeats blueprint macrostructure. Our explains robustness folding common core, dynamic gene regulation overlaid across cells.

Language: Английский

Citations

160
Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis DOI Open Access
Raymond Chen, Charles A. Ishak, Daniel D. De Carvalho

et al.

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(11), P. 2707 - 2725

Published: Oct. 14, 2021

Abstract Features of the cancer epigenome distinguish cancers from their respective cell origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition DNA- or histone-modifying enzymes. Epigenetic therapies converge with immunotherapies “viral mimicry,” a cellular state active antiviral response triggered by endogenous nucleic acids often derived aberrantly transcribed retrotransposons. This review describes initial characterization expansion viral mimicry–inducing approaches as well features “prime” for mimicry induction. Increased understanding in contexts suggests potential physiologic roles homeostasis. Significance: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels cancer-specific vulnerability beyond tolerable thresholds to induce signaling increase dependence on dsRNA stress responses mediated ADAR1. Improved tolerance mechanisms reveals synergistic treatment combinations epigenetic include BCL2, ADAR1, immune checkpoint blockade. Further may identify maximize efficacy conventional therapies.

Language: Английский

Citations

129
Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos DOI Creative Commons
Chuan Chen, Wenqiang Liu, Jiayin Guo

et al.

Protein & Cell, Journal Year: 2021, Volume and Issue: 12(6), P. 455 - 474

Published: April 22, 2021

Abstract N 6 -methyladenosine (m A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but intrinsic mechanism remains unclear. Here, we report that YTHDC1 indispensable self-renewal differentiation potency of mouse embryonic stem cells (ESCs), which highly depends m A-binding ability. Ythdc1 is required for sufficient rRNA synthesis repression 2-cell (2C) transcriptional program ESCs, recapitulates transcriptome regulation by LINE1 scaffold. Detailed analyses revealed recognizes A nucleus regulates formation LINE1-NCL partnership recruitment KAP1. Moreover, establishment H3K9me3 2C-related retrotransposons interrupted -depleted ESCs inner cell mass (ICM) cells, consequently increases activities. Our study reveals a role regulating RNA scaffold, providing new model RNA-chromatin cross-talk.

Language: Английский

Citations

114
Inflammation and DNA damage: cause, effect or both DOI
Antonio Pezone, Fabiola Olivieri,

Maria Vittoria Napoli

et al.

Nature Reviews Rheumatology, Journal Year: 2023, Volume and Issue: 19(4), P. 200 - 211

Published: Feb. 7, 2023

Language: Английский

Citations

102
Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development DOI Creative Commons
Ariane Lismer, Sarah Kimmins

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 14, 2023

Abstract Although more studies are demonstrating that a father’s environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought sperm exclusively contributed its genome to egg. More recently, association have shown various environmental exposures including poor diet, toxicants, stress, perturbed epigenetic marks in at important reproductive developmental loci were associated with offspring phenotypes. The cellular routes underlie how transmitted fertilization, resist reprogramming embryo, drive phenotypic changes only now beginning be unraveled. Here, we provide an overview of state field intergenerational paternal mammals present new insights into relationship between embryo development three pillars inheritance: chromatin, DNA methylation, non-coding RNAs. We evaluate compelling evidence sperm-mediated transmission retention embryo. Using landmark examples, discuss sperm-inherited regions may escape impact via implicate transcription factors, chromatin organization, transposable elements. Finally, link paternally functional pre- post-implantation Understanding factors will permit greater understanding related origins disease.

Language: Английский

Citations

78
Phase separation of RNA-binding protein promotes polymerase binding and transcription DOI

Wen Shao,

Xianju Bi, Yixuan Pan

et al.

Nature Chemical Biology, Journal Year: 2021, Volume and Issue: 18(1), P. 70 - 80

Published: Dec. 16, 2021

Language: Английский

Citations

102
ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation DOI Creative Commons
Richard de Reuver, Evelien Dierick, Bartosz Wiernicki

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 36(6), P. 109500 - 109500

Published: Aug. 1, 2021

Loss of function adenosine deaminase acting on double-stranded RNA (dsRNA)-1 (ADAR1) causes the severe autoinflammatory disease Aicardi-Goutières syndrome (AGS). ADAR1 converts adenosines into inosines within dsRNA. This process called A-to-I editing masks self-dsRNA from detection by antiviral dsRNA sensor MDA5. binds to in both canonical A-form and poorly defined Z conformation (Z-RNA). Mutations Z-RNA-binding Zα domain are common patients with AGS. How loss ADAR1/Z-RNA interaction contributes development is unknown. We demonstrate that abrogated binding Z-RNA leads reduced structures formed base pairing inversely oriented short interspersed nuclear elements. Preventing triggers an MDA5/MAVS-mediated type I interferon response lethal autoinflammation mice. shows between restricts sensing prevents AGS development.

Language: Английский

Citations

92
Close to the edge: Heterochromatin at the nucleolar and nuclear peripheries DOI

Aizhan Bizhanova,

Paul D. Kaufman

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Journal Year: 2020, Volume and Issue: 1864(1), P. 194666 - 194666

Published: Dec. 8, 2020

Language: Английский

Citations

82
LINE1 are spliced in non-canonical transcript variants to regulate T cell quiescence and exhaustion DOI
Federica Marasca, Shruti Sinha, Rebecca Vadalà

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(2), P. 180 - 193

Published: Jan. 17, 2022

Language: Английский

Citations

63