Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions

Yang, Bo; Fang, Lu; Gao, Qianqian; Xu, Ce; Xu, Junqin; Chen, Zhenxia; Wang, Yixuan; Yang, Peng

doi:10.1073/pnas.2119415119

Cited by 11 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, it is unclear from our data what role repressive factors play in regulating HERV expression. Zinc finger proteins are known regulators of HERVs, via their ability to identify and bind motifs in the LTR and the PBS [ 57 – 59 ]. The KRAB-ZFPs have been reported to regulate DNA methylation and histone modification of HERVs through the recruitment of proteins such as KAP1/TRIM28 [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues

Burn

Roy²,

Freeman³

et al. 2022

PLoS Biol

View full text Add to dashboard Cite

Human endogenous retrovirus (HERV) transcripts are known to be highly expressed in cancers, yet their activity in nondiseased tissue is largely unknown. Using the GTEx RNA-seq dataset from normal tissue sampled at autopsy, we characterized individual expression of the recent HERV-K (HML-2) provirus group across 13,000 different samples of 54 different tissues from 948 individuals. HML-2 transcripts could be identified in every tissue sampled and were elevated in the cerebellum, pituitary, testis, and thyroid. A total of 37 different individual proviruses were expressed in 1 or more tissues, representing all 3 LTR5 subgroups. Nine proviruses were identified as having long terminal repeat (LTR)-driven transcription, 7 of which belonged to the most recent LTR5HS subgroup. Proviruses of different subgroups displayed a bias in tissue expression, which may be associated with differences in transcription factor binding sites in their LTRs. Provirus expression was greater in evolutionarily older proviruses with an earliest shared ancestor of gorilla or older. HML-2 expression was significantly affected by biological sex in 1 tissue, while age and timing of death (Hardy score) had little effect. Proviruses containing intact gag, pro, and env open reading frames (ORFs) were expressed in the dataset, with almost every tissue measured potentially expressing at least 1 intact ORF (gag).

show abstract

Section: Discussionmentioning

confidence: 99%

Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues

Burn

Roy²,

Freeman³

et al. 2022

PLoS Biol

View full text Add to dashboard Cite

show abstract

“…Additionally, it is unclear from our data what role repressive factors play in regulating HERV expression. Zinc finger proteins are known regulators of HERVs, via their ability to identify and bind motifs in the LTR and the PBS (Iouranova et al, 2022; Wolf et al, 2015; Yang et al, 2022). The KRAB-ZFPs have been reported to regulate DNA methylation and histone modification of HERVs through the recruitment of proteins such as KAP1/TRIM28 (Rowe et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The HERV-K(HML-2) Transcriptome in Non-Diseased Tissue

Burn

Roy²,

Freeman

et al. 2022

Preprint

View full text Add to dashboard Cite

Human endogenous retrovirus (HERV) transcripts are known to be highly expressed in can-cers, yet their activity in non-diseased tissue is largely unknown. Using the GTEx RNA-seq da-taset from normal tissue sampled at autopsy, we characterized individual expression of the recent HERV-K(HML-2) provirus group across 13,000 different samples of 54 different tissues from 948 individuals. HML-2 transcripts could be identified in every tissue sampled, and were elevated in the cerebellum, pituitary, testis, and thyroid. 37 different individual proviruses were expressed in one or more tissues, representing all three LTR5 subgroups. 9 proviruses were identified as having LTR-driven transcription, 7 of which belonged to the most recent LTR5HS subgroup. Proviruses of different subgroups displayed a bias in tissue expression which may be associated with differences in transcription factor binding sites in their LTRs. Provirus expression was greater in evolutionarily older proviruses with an earliest shared an-cestor of gorilla or older. HML-2 expression was significantly affected by biological sex in one tissue, while age and timing of death (Hardy score) had little effect. Proviruses containing in-tact gag, pro and env ORFs were expressed in the dataset, with almost every tissue measured potentially expressing at least one intact ORF (gag).

show abstract

“…In the field, an outstanding question is how different ERVs are targeted and repressed in physiological conditions. Although a few KRAB zinc-finger proteins such as ZFP809 and ZFP961 are identified for transcriptional silence of specific REs, other TFs remained to be determined (Imbeault et al, 2017; Tan et al, 2013; Wolf and Golf, 2009; Yang et al, 2022). In this work, we showed that POGZ binds to certain REs in a DNA sequence specific manner, analogous to KRAB zinc finger (KRAB-ZnF) proteins such as ZF809 and ZFP819.…”

Section: Discussionmentioning

confidence: 99%

POGZ suppresses 2C transcriptional program and retrotransposable elements

Sun

Zhang

Cheng

et al. 2022

Preprint

View full text Add to dashboard Cite

ThePOGZgene has been found frequently mutated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). We have recently shown that POGZ maintains mouse embryonic stem cells (ESCs) as a chromatin regulator and a transcription factor. However, the exact mechanisms remain unclear. Here we show that POGZ plays important role in the maintenance of ESCs by silencing theDuxgene and certain endogenous retroviruses (ERVs). POGZ directly binds to theDuxgene and ERVs, and its depletion leads to up-regulation of 2C genes and the repetitive elements such as RLTR9E and IAP (the intracisternal A-type particles), resulting in transition to a 2C-like (2CLC) state and genome instability. POGZ regulates ESC heterochromatin state by association and recruiting TRIM28 and SETDB1, and its loss leads to increased H3K4me3 and H3K27ac, and decreased H3K9me3 at local chromatin. Activation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes. Chimeric transcripts that are initiated within ERVs and spliced to genic exons are highly expressed inPogz−/−ESCs. Our findings establish that POGZ is required for the maintenance of ESCs by repressingDuxand silencing ERVs, which may provide important insights into the disease pathology caused by POGZ dysfunction.HighlightsPOGZ depletion leads to activation of 2C genesPOGZ depletion leads to deregulation of ERVsPOGZ directly binds and repressesDuxPOGZ associates with TRIM28/SETDB1 to maintain heterochromatin state to silence ERVsActivation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes

show abstract

Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions

Cited by 11 publications

References 35 publications

Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues

Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues

The HERV-K(HML-2) Transcriptome in Non-Diseased Tissue

POGZ suppresses 2C transcriptional program and retrotransposable elements

Contact Info

Product

Resources

About