Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses

AbstractColorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

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The Maize Unstable factor for orange1 Is a Dominant Epigenetic Modifier of a Tissue Specifically Silent Allele of pericarp color1

Genetics ◽

10.1093/genetics/163.3.1135 ◽

2003 ◽

Vol 163 (3) ◽

pp. 1135-1146 ◽

Cited By ~ 3

Author(s):

Surinder Chopra ◽

Suzy M Cocciolone ◽

Shaun Bushman ◽

Vineet Sangar ◽

Michael D McMullen ◽

...

Keyword(s):

Dna Sequences ◽

Somatic Mosaicism ◽

Methylation State ◽

Vegetative Tissues ◽

Epigenetic Modifier ◽

Gene Copies ◽

Allele Specific ◽

Silent Allele ◽

Methylation Patterns ◽

Variable Penetrance

Abstract We have characterized Unstable factor for orange1 (Ufo1), a dominant, allele-specific modifier of expression of the maize pericarp color1 (p1) gene. The p1 gene encodes an Myb-homologous transcriptional activator of genes required for biosynthesis of red phlobaphene pigments. The P1-wr allele specifies colorless kernel pericarp and red cobs, whereas Ufo1 modifies P1-wr expression to confer pigmentation in kernel pericarp, as well as vegetative tissues, which normally do not accumulate significant amounts of phlobaphene pigments. In the presence of Ufo1, P1-wr transcript levels and transcription rate are increased in kernel pericarp. The P1-wr allele contains approximately six p1 gene copies present in a hypermethylated and multicopy tandem array. In P1-wr Ufo1 plants, methylation of P1-wr DNA sequences is reduced, whereas the methylation state of other repetitive genomic sequences was not detectably affected. The phenotypes produced by the interaction of P1-wr and Ufo1 are unstable, exhibiting somatic mosaicism and variable penetrance. Moreover, the changes in P1-wr expression and methylation are not heritable: meiotic segregants that lack Ufo1 revert to the normal P1-wr expression and methylation patterns. These results demonstrate the existence of a class of modifiers of gene expression whose effects are associated with transient changes in DNA methylation of specific loci.

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PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads

Genome Biology ◽

10.1186/s13059-021-02307-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Maria Artesi ◽

Vincent Hahaut ◽

Basiel Cole ◽

Laurens Lambrechts ◽

Fereshteh Ashrafi ◽

...

Keyword(s):

Viral Genome ◽

Clonal Expansion ◽

Endogenous Retroviruses ◽

Viral Genomes ◽

Short Read Sequencing ◽

Long Reads ◽

Infected Cells ◽

Insertion Sites ◽

Viral Insertion ◽

Hiv 1

AbstractThe integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

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