scholarly journals Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

2019 ◽  
Author(s):  
Priscilla Turelli ◽  
Christopher Playfoot ◽  
Dephine Grun ◽  
Charlène Raclot ◽  
Julien Pontis ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Embryonic Stem ◽  
Zinc Finger Proteins ◽  
Endogenous Retrovirus ◽  
Adult Brain ◽  
Human Endogenous Retrovirus ◽  
Regulatory Sequences ◽  
Human Neurons ◽  
And Function ◽  
Transcription Networks

AbstractIn the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs). Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.One Sentence SummaryYoung transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons.

scholarly journals Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

2020 ◽  
Vol 6 (35) ◽  
pp. eaba3200
Author(s):  
Priscilla Turelli ◽  
Christopher Playfoot ◽  
Dephine Grun ◽  
Charlène Raclot ◽  
Julien Pontis ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Embryonic Stem ◽  
Zinc Finger Proteins ◽  
Endogenous Retrovirus ◽  
Adult Brain ◽  
Human Endogenous Retrovirus ◽  
Regulatory Sequences ◽  
Control Gene Expression ◽  
Human Neurons ◽  
Transcription Networks

In the first days of embryogenesis, transposable element–embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB) zinc finger proteins (KZFPs). Many TEeRS are subsequently co-opted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESCs). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.

Human endogenous retrovirus protein Rec interacts with the testicular zinc-finger protein and androgen receptor

2010 ◽  
Vol 91 (6) ◽  
pp. 1494-1502 ◽  
Author(s):  
S. Kaufmann ◽  
M. Sauter ◽  
M. Schmitt ◽  
B. Baumert ◽  
B. Best ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Finger Protein

scholarly journals Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes

2019 ◽  
Author(s):  
Weiyu Zhang ◽  
Fuquan Chen ◽  
Ruiqing Chen ◽  
Dan Xie ◽  
Jiao Yang ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Embryonic Stem ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Enhancer Activity ◽  
Cell Cleavage ◽  
Cell Embryo ◽  
And Function ◽  
Scan Domain

AbstractEndogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.

scholarly journals ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

2021 ◽  
Author(s):  
Chunhong Yu ◽  
Xiaoyun Lei ◽  
Fang Chen ◽  
Song Mao ◽  
Lu Lv ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tumor Suppressors ◽  
Target Genes ◽  
Critical Role ◽  
Endogenous Retrovirus ◽  
Early Embryogenesis ◽  
Human Endogenous Retrovirus ◽  
Regulatory Sequences ◽  
3D Architecture

The transposable elements (TEs) through evolutionary exaptation have become an integral part of human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis are recognized, their role in malignancy has only started to emerge. Here we show that many TEs, especially the pluripotency-related endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. The transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors including ARID1A. Knockout of ARID1A in CRC cells leads to increased accessibility at HERVH loci and enhanced transcription, which is dependent on ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulate their dynamics, and co-regulate many target genes. Altogether, we uncover a critical role for ARID1A in restraining HERVH, which can promote tumorigenesis by stimulating BRD4-dependent transcription when ARID1A is mutated.

scholarly journals Non-essential function of KRAB zinc finger gene clusters in retrotransposon suppression

2020 ◽  
Author(s):  
Gernot Wolf ◽  
Alberto de Iaco ◽  
Ming-An Sun ◽  
Melania Bruno ◽  
Matthew Tinkham ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Germ Line ◽  
Es Cells ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Gene Clusters ◽  
Endogenous Retrovirus ◽  
Segmental Duplications ◽  
Transposon Silencing

AbstractThe Krüppel-associated box zinc finger protein (KRAB-ZFP) family amplified and diversified in mammals by segmental duplications, but the function of the majority of this gene family remains largely unexplored due to the inaccessibility of the gene clusters to conventional gene targeting. We determined the genomic binding sites of 61 murine KRAB-ZFPs and genetically deleted in mouse embryonic stem (ES) cells five large KRAB-ZFP gene clusters encoding nearly one tenth of the more than 700 mouse KRAB-ZFPs. We demonstrate that clustered KRAB-ZFPs directly bind and silence retrotransposons and block retrotransposon-borne enhancers from gene activation in ES cells. Homozygous knockout mice generated from ES cells deleted in one of two KRAB-ZFP clusters were born at sub-mendelian frequencies in some matings, but heterozygous intercrosses could also yield knockout progeny with no overt phenotype. We further developed a retrotransposon capture-sequencing approach to assess mobility of the MMETn family of endogenous retrovirus like elements, which are transcriptionally activated in KRAB-ZFP cluster KOs, in a pedigree of KRAB-ZFP cluster KO and WT mice. We identified numerous somatic and several germ-line MMETn insertions, and found a modest increase in activity in mutant animals, but these events were detected in both wild-type and KO mice in stochastic and highly variable patterns. Our data suggests that the majority of young KRAB-ZFPs play a non-essential role in transposon silencing, likely due to the large redundancy with other KRAB-ZFPs and other transposon restriction pathways in mice.One Sentence SummaryMegabase-scale deletions of KRAB-ZFP gene clusters in mice leads to retrotransposon activation.

scholarly journals The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

2018 ◽  
Author(s):  
Serge Nataf ◽  
Juan Uriagereka ◽  
Antonio Benitez-Burraco
Keyword(s):  
Intellectual Disability ◽  
Protein Sequences ◽  
Autism Spectrum ◽  
Endogenous Retrovirus ◽  
Human Cognition ◽  
Human Endogenous Retrovirus ◽  
Signal Transducer ◽  
Long Terminal Repeats ◽  
Promoter Regions ◽  
Human Neurons

ABSTRACTSocial behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFNγ). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFNγ pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retrovirus). However, the putative role of an IFNγ/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFNγ, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, functionally-relevant differences between humans and chimpanzees are observed regarding the 3 main components of this pathway: i) the protein sequences of immunes TFs binding MER41 LTRs, ii) the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes and iii) the protein sequences of the targeted ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Together, these results suggest that the stepped self-domestication of MER41 in the genomes of primates could have been a driver of cognitive evolution. Our data further indicate that non-inherited forms of ID might result from alterations of the immune/MER41/cognition pathway induced notably by the untimely or quantitatively inappropriate exposure of human neurons to IL-6.

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