Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression

Ito, Jumpei; Kimura, Izumi; Soper, Andrew; Coudray, Alexandre; Koyanagi, Yoshio; Nakaoka, Hirofumi; Inoue, Ituro; Turelli, Priscilla; Trono, Didier; Sato, Kei

doi:10.1126/sciadv.abc3020

Cited by 44 publications

(55 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TEeRS can act as enhancers, repressors, promoters, terminators, insulators or via post-transcriptional mechanisms (Garcia-Perez et al 2016;Chuong et al 2017). Although these co-opted TE functions are key to human biology, their deregulation can also contribute to pathologies such as cancer and neurodegenerative diseases (Li et al 2015;Chuong et al 2016;Attig et al 2019;Jang et al 2019;Ito et al 2020;Jönsson et al 2020).…”

mentioning

confidence: 99%

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

et al. 2021

Self Cite

View full text Add to dashboard Cite

Transposable elements (TEs) account for more than 50% of the human genome and many have been co-opted throughout evolution to provide regulatory functions for gene expression networks. Several lines of evidence suggest that these networks are fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed “transposcription”) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. To elucidate the spatiotemporal transposcriptome of the developing human brain, we have analyzed two independent RNA-seq data sets encompassing 16 brain regions from eight weeks postconception into adulthood. We reveal a distinct KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type–specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. Long-read sequencing confirmed these TE-driven isoforms as significant contributors to neurogenic transcripts. We also show experimentally that a co-opted antisense L2 element drives temporal protein relocalization away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its importance throughout TE mediated genome innovation and neurotypical human brain development. To facilitate interactive exploration of these spatiotemporal gene and TE expression dynamics, we provide the “Brain TExplorer” web application freely accessible for the community.

show abstract

mentioning

confidence: 99%

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…It seems that cancer and immune diseases are not accompanied by transcriptional activation of all HERVs, but rather the upregulation of specific HERV loci in different diseases was observed. Other studies described a more global activation of HERV especially in solid tumor samples ( 25 ). Nevertheless, different tumor entities could be classified according to their HERV expression ( 25 ) suggesting entity specific expression pattern.…”

Section: Discussionmentioning

confidence: 97%

“…Other studies described a more global activation of HERV especially in solid tumor samples ( 25 ). Nevertheless, different tumor entities could be classified according to their HERV expression ( 25 ) suggesting entity specific expression pattern. Due to the large group of HERVK it cannot be excluded that the differential expression of single loci is not detected by our evaluation.…”

Section: Discussionmentioning

confidence: 97%

“…In addition to direct effects of HERV products, HERV-related sequences in the genome can have the ability to control genes in coordinated networks of transcriptional regulation. HERV can act as cis-regulatory elements ( 24 , 25 ), produce non-coding RNAs that influence nearby genes and/or the global transcriptome in trans ( 26 , 27 ), and alternate the epigenetic landscape in cancer cells ( 28 , 29 ). For example, HERVK and HERVH have been shown to influence the transcription of genes involved in pluripotency ( 30 , 31 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Differentially Expressed Human Endogenous Retrovirus Families in Human Leukemia and Lymphoma Cell Lines and Stem Cells

et al. 2021

View full text Add to dashboard Cite

Endogenous retroviruses (ERVs) are becoming more and more relevant in cancer research and might be potential targets. The oncogenic potential of human ERVs (HERVs) has been recognized and includes immunosuppression, cell fusion, antigenicity of viral proteins, and regulation of neighboring genes. To decipher the role of HERVs in human cancers, we used a bioinformatics approach and analyzed RNA sequencing data from the LL-100 panel, covering 22 entities of hematopoietic neoplasias including T cell, B cell and myeloid malignancies. We compared HERV expression in this panel with hematopoietic stem cells (HSCs), embryonic stem cells (ESCs) and normal blood cells. RNA sequencing data were mapped against a comprehensive synthetic viral metagenome with 116 HERV sequences from 14 different HERV families. Of these, 13 HERV families and elements were differently expressed in malignant hematopoietic cells and stem cells. We found transcriptional upregulation of HERVE family in acute megakaryocytic and erythroid leukemia and of HERVFc family in multiple myeloma/plasma cell leukemia (PCL). The HERVFc member HERVFc-1 was found transcriptionally active in the multiple myeloma cell line OPM-2 and also in the Hodgkin lymphoma cell line L-428. The expression of HERVFc-1 in L-428 cells was validated by qRT-PCR. We also confirm transcriptional downregulation of ERV3 in acute megakaryocytic and erythroid leukemia, and HERVK in acute monocytic and myelocytic leukemia and a depression of HERVF in all malignant entities. Most of the higher expressed HERV families could be detected in stem cells including HERVK (HML-2), HERV-like, HERVV, HERVT, ERV9, HERVW, HERVF, HERVMER, ERV3, HERVH and HERVPABLB.

show abstract

“…TEeRS can act as enhancers, repressors, promoters, terminators, insulators or via post-transcriptional mechanism (Garcia-Perez et al 2016;Chuong et al 2017). While these co-opted TE functions are key to human biology, their deregulation can also contribute to pathologies such as cancer and neurodegenerative diseases (Jang et al 2019;Attig et al 2019;Chuong et al 2016;Li et al 2015;Ito et al 2020;Jönsson et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Playfoot

Duc

Sheppard

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Transposable elements (TEs) constitute 50% of the human genome and many have been co-opted throughout human evolution due to gain of advantageous regulatory functions controlling gene expression networks. Several lines of evidence suggest these networks can be fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed ‘transposcription’) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking.In order to elucidate the spatiotemporal transposcriptome of the developing human brain, we have analysed two independent RNA-seq datasets encompassing 16 distinct brain regions from eight weeks post-conception into adulthood. We reveal an anti-correlated, KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. We also demonstrate experimentally that a co-opted antisense L2 element drives temporal protein re-localisation away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its potential importance throughout neurotypical human brain development.

show abstract

Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression

Cited by 44 publications

References 60 publications

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Identification of Differentially Expressed Human Endogenous Retrovirus Families in Human Leukemia and Lymphoma Cell Lines and Stem Cells

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Contact Info

Product

Resources

About