Publisher Correction: Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Mehdipour, Parinaz; Marhon, Sajid A.; Ettayebi, Ilias; Chakravarthy, Ankur; Hosseini, Amir; Wang, Yadong; Castro, Fabíola Attié de; Yau, Helen Loo; Ishak, Charles A.; Abelson, Sagi; O’Brien, Catherine A.; Carvalho, Daniel D De

doi:10.1038/s41586-021-03329-1

Cited by 7 publications

(12 citation statements)

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“…2b and 2e ). Alu SINEs, specifically inverted-repeat Alu (IR-Alu) elements, are a major source of double-stranded RNA that can activate innate and adaptive immune response[24, 25]. To characterize transcription and epigenetic changes at IR-Alu elements by co-inhibition of DNMT and HDAC, we first selected the transcriptionally active IR-Alu from all IR-Alu elements present in the human genome (with sum of RNA-seq reads from DMSO and DNMT-HDACi samples ≥5, see Method for details, resulting in total of 4966, 83952, and 84606 active IR-Alus in GP5d, OE19, and GP5d p53-KO cells, respectively) and analyzed the changes in their expression between the DNMTi-HDACi- and vehicle-treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…TE-derived dsRNA activates immunogenic response [24,25] and the IR-Alus are the major source of the dsRNA [24,47]. ADAR1 enzymes edit dsRNA from IR-Alus to inhibit activation immunogenic response [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

“…2b and 2e). Alu SINEs, specifically inverted-repeat Alu (IR-Alu) elements, are a major source of double-stranded RNA that can activate innate and adaptive immune response 24,25 .…”

Section: Gp5d and Oe19 Cellsmentioning

confidence: 99%

“…The IR-Alu for human genome reported in ref. [24] was shared by Dr. Parinaz Mehdipour and genomic coordinates were converted from hg19 to hg38 assembly by using liftOver tool[81].…”

Section: Ir-alu Expression Analysismentioning

confidence: 99%

“…Previous studies have shown that human endogenous retrovirus (HERV) elements from the LTR12C subfamily derepressed by DNMTi or DNMTi-HDACi mainly contribute to immunogenic TE-chimeric transcripts [21,22]. Moreover, inhibition of DNMT induces expression of TEs that can form double-stranded RNA (dsRNA) to activate type I/III interferon response [24][25][26][27]. Derepressed TE-derived dsRNA induces viral mimicry that can make cancer cells sensitive to immune therapy [25,28].…”

Section: Introductionmentioning

confidence: 99%

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Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Patel,

Tiusanen,

Pihlajamaa

et al. 2024

Preprint

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The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…2b and 2e). Alu SINEs, specifically inverted-repeat Alu (IR-Alu) elements, are a major source of double-stranded RNA that can activate innate and adaptive immune response 24,25 .…”

Section: Gp5d and Oe19 Cellsmentioning

confidence: 99%

“…The IR-Alu for human genome reported in ref. [24] was shared by Dr. Parinaz Mehdipour and genomic coordinates were converted from hg19 to hg38 assembly by using liftOver tool[81].…”

Section: Ir-alu Expression Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Patel,

Tiusanen,

Pihlajamaa

et al. 2024

Preprint

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MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA

Valle

Singh

et al. 2021

Nat Commun

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Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease.

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DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Goyal,

Bauer,

Hey

et al. 2023

Nat Commun

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Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase inhibitor (HDACi), to assemble a de novo transcriptome and identify several thousand ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs). Using immunopeptidomics, we demonstrate the human leukocyte antigen (HLA) presentation of 45 spectra-validated treatment-induced neopeptides (t-neopeptides) arising from TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response to effectively target cancer cells. We further verify the presence of t-neopeptides in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight the potential of ERV-derived neoantigens in epigenetic and immune therapies.

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Publisher Correction: Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency

Cited by 7 publications

References 0 publications

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

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