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A zebrafish reporter line reveals immune and neuronal expression of endogenous retrovirus

21 Jan 2021-bioRxiv (Cold Spring Harbor Laboratory)-

Abstract: Endogenous retroviruses (ERVs) are fossils left in our genome from retrovirus infections of the past. Their sequences are part of every vertebrate genome and their random integrations are thought to have contributed to evolution. Although ERVs are mainly kept silenced by the host genome, they are found activated in multiple disease states such as auto-inflammatory disorders and neurological diseases. What makes defining their role in health and diseases challenging is the numerous copies in mammalian genomes and the lack of tools to study them. In this study, we identified 8 copies of the zebrafish endogenous retrovirus (zferv). We created and characterised the first in vivo ERV reporter line in any species. Using a combination of live imaging, flow cytometry and single cell RNA sequencing, we mapped zferv expression to early T cells and neurons. Thus, this new tool identified tissues expressing ERV in zebrafish, highlighting a potential role of ERV during brain development and strengthening the hypothesis that ERV play a role in immunity and neurological diseases. This transgenic line is therefore a suitable tool to study the function of ERV in health and diseases. Funding This work has been supported by a European Leukodystrophy Association fellowship (ELA 2016-012F4) to NH, an MRC Programme Grant (MR/M004864/1) to SAR and . JPL is supported by Agence Nationale de la Recherche (grant ANR-16-CE20-0002-03.. Imaging was carried out in the Wolfson Light Microscopy Facility, supported by an MRC grant (G0700091) and a Wellcome Trust grant (GR077544AIA). Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Topics: Endogenous retrovirus (60%)

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A"zebrafish"reporter"line"reveals"immune"and"neuronal"expression"of"endogenous"
retrovirus."
!
Noémie! Hamilton
1,2
*,! Amy! Clarke
1
,! Hannah!Isles
1
,! Euan! Carson
1
,!Jean-Pierre!Levraud
3
,!
Stephen!A!Renshaw
1!
!
!
1.
!
The!Bateson!Centre,!Department!of!Infection,!Immunity!and!Cardiovascular!Disease,!
University!of!Sheffield,!Sheffield,!UK!
2.!The!Institute!of!Neuroscience,!University!of!Sheffield,!Sheffield,!UK!
3.!Macrophages!et!veloppement!de!l’Immunité,!Institut!Pasteur,!CNRS!UMR3738,!25!
rue!du!docteur!Roux,!75015!Paris!!
!
*Corresponding!author:!n.m.hamilton@sheffield.ac.uk
!
"
Abstract"
"
Endogenous!retroviruses!(ERVs)!are!fossils!left!in!our!genome!from!retrovirus!infections!
of! the! past.! Their! sequences! are! part! of! every! vertebrate! genome! and! their! random!
integrations!are!thought!to!have!contributed!to!evolution.!Although!ERVs!are!mainly!kept!
silenced!by!the!host! genome,!they!are!found! a ctivated!in!mult iple!disease!stat es!such!as!
auto-in flammat ory! d isorders!and!neurological!diseases.!What!makes!defining!their!role!
in!health!and!diseases!challenging!is!the!numerous!copies!in!mammalian!genomes!and!
the! lack! of! tools! to! study! them.! In!this! study,! we! identified! 8! cop i es! of! the!zebrafish!
endogenous! retrovirus!(!"#$%).!We!created!and!characterised!the!first!&'(%&%)!ERV!reporter!
line!in!any!species.!Using!a!combination!of!live!imaging,!flow!cytometry!and!single!cell!
RNA!sequencing,!we!mapped!!"#$%!expression!to!early!T!cells! and!neurons.!Thus,!this!new!
tool!identified!tissues!expressing!ERV!in !zebrafish,!highlighting!a !p oten t ial!role!of!ERV!
during! brain! devel opment! and! strengthening! the! hypothesis! that! ERV! play! a! role! in!
immunity!and!neurological!diseases.!This!transgen ic!line!is!therefore!a!suitable!tool!to!
study!the!funct ion!of!ERV!in!health!and!diseases.!
"
Keywords"
Retroelement,!zebrafish,!endogenous!retrovirus,!reporter!line,!!"#$%,!LTR!
"
Funding"
This! work! has! been! supported! by! a! European! Leukodystrophy! Association! fellowship!
(ELA!2016-012F4)! to!NH,!an!MRC!Programme!Grant! (MR/M004864/1)!to!SAR! and!.!JPL!
is! supported! by! Agence! Nat ionale! de! la! R echerche! ( grant! ANR-16-CE20 -0002-03..!
Imaging!was!ca rried!out! i n!t he!Wolfson!Light!M i croscopy!Facility,!supported!by!an!MRC!
grant!( G0700091)!and!a!Wellcome!Trust!grant !(GR077544AIA).!!
"
Conflict"of"Interest"Statement"
The! authors!declare!that!the!research!was!conducted!in!the!absence!of!any!commercial!or!
financial!relationships !that!could!be!construed!as!a!potential!conflict!of!interest.!
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.CC-BY-NC-ND 4.0 International licenseperpetuity. It is made available under a
preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
The copyright holder for thisthis version posted January 21, 2021. ; https://doi.org/10.1101/2021.01.21.427598doi: bioRxiv preprint

Introduction"
"
Over!40%!of!the!human!genome!comprises!endogenous!transposable!elements!capable!
of!recombination!and!disruption!of!genes!and!modification!of!their!expression!(Lander!et!
al.!2001).!Endogenous!retroviruses!(ERVs)!are!transposable!elements!originating!from!
old!integrations!of!retroviruses!so!successful!that!they!have!become!part!of!all!vertebrate!
genomes!st udied.!ERVs!replicate!autonomously!using!a!copy-and-pa ste!mechanism!and!
although!they! form!a!smaller!percentage!of! all!retroelements,!they!still!represent !8%!of!
the!human!genome!(Bourque!et!al.!2018;!Lander!et!al.!2001).! The!majority!of!known!ERVs!
have! lost! their! ability! to! replicate,! but! those! most! recently! acquired! still! h ave! intac t !
genomes! with!the!ability! to!produce!viral! RNA!and!particles.! However,!these! competent!
ERVs!are!under!strict!transcriptional!suppression!by!epigenetic! mechanisms!(Maksakova,!
Mager,! and! Reiss! 2008;! Rowe! et! al.! 2010;! Turelli! et! al.! 2014),! protecting! the! host!
organisms!against!potential!retroviral!insertions!and!viral!activities.!!!
!
Although!immobilised!by!mutations!or!transcriptiona lly!repressed,!ERVs!have!a!complex!
relationship!with!the!human!genome,!which!they!can!regulate!by!providing!cis-regulatory!
elements! to! surrounding! genes! and! by! lifting! their! transcriptionally! repressed! state.!
Through!these!mechanisms,!it!is!believed!that!transposable!elements!have!fuelled!some!
of! the! necessary!genetic!changes!for!evolution! (Feschotte!2008;!Kunarso!et!al.!2010).!!
*+',+-&'./,!an!ERV!envelope!gene! essential! for!the! vascularisation!of!the!placenta,! is! at!the!
origin! of! evolutionary! diversification! of! the! placenta! (Chuong! 2018;! Mi! et! al.! 2000).!
During!human!embryogenesis,!expression!of!specific!ERV!families!have!been!associated!
with!cell!identity!and!cell!pot ency!in!ea rly!stem!cells!(Göke!et!al.!2015).!Additionally,!ERV!
expression!has!been!reported!in!healthy!human!tissues!such!as!ovary!and!testis!for!ERV-
9! (Pi! et! al.! 2004),! pancreas! (Shiroma! et! al.! 2001),! breast! (Tavakolian,! Goudarzi,! and!
Faghihl oo!2019),! stomach! and! small! intestine! (Okahara!et!al.!2004).! Mainly! based! on!
transcriptional!studies,!the!expression!of!different!families!of!ERV!is!likely!to!be!extended!
to!more!tissues,!however!their!role!in!tissue!development!and!function!remains!largely!
unknown.!!
!
ERVs! have! been! linked! directly! and! indirectly! to! the! evolution! and! functioning! of! the!
immune!system.!Enhancer!regions!of!interferon!stimulated!genes!key!to!the!interferon!
pathway,!such!as!IRF1!and!STAT1,! were!found! i ntroduced! and!amplified!by!ERV! elements,!
with!the!human! inflammasome! failing!to!form! upon! the!deletion! of!a !subset! of!ERVs!
(Chuong,!Elde,!a nd! Feschotte!2 016) .!Ad aptive!immunity!also!benefits!from!the!presence!
of!ERVs.!Indeed,!ERV!peptide!recognition!is!used! in!T!cell !selection!to!optimise!antigen!
recognition! and! T! cells! have! a! higher! sensitivity! to! exogenous! virus! infection! when!
presented !with! ERV!peptides! during! their!initial!thymic!selection ! (Mandl! et! al.! 2013;!
Young!et!al.!2012).!The!human!ERV!(HERV)!envelope!gene!contains!immunosuppressive!
domains!that!reduce!the!Th1!response!during!pregnancy!and!therefore!promote!foetal!
development!(Knerr!et!al.! 2004;!Lokossou!et!al.! 2020).!The!role!of!ERVs!in!our!immune !
system,!particula rly!in!the!training!of!our!adap tive!immunity,!can!be!a!double-edge!sword!
as!ERVs!are!linked!to!a!range!of!different!disease!states,!including!autoimmunity.!!
!
Aberrant! expression! of! ERVs! contributes! to! multiple! pathologies.! ERVs! are! found! in!
abundance!in!multiple!forms!of!cancers!and!are!considered!tumour-promoting!fa ctors!
(extensively! reviewed! in! (Bermejo! et! al.! 2020).! The! pathology! of! auto-inflammatory!
diseases! has! also! been! strongly! associated! with! ERVs.! Syst emic! l upus! erythematosus!
(SLE)! is! an! autoimmune! disorder! with! increased! level! of! autoantigen! for! an! ERV!
(Jorgensen!et!al.!2014).! Recently,! one!of!the!murine! SLE! susceptibility!locus!was!i dentified!
as!a!key!suppressor!of!ERV!expression,!consolidating!the!role!of!ERVs!in!the!pathogenesis!
of!SLE!(Treger!et!al.!2019).!A!similar!disorder!is!Acardi-Goutieres!Syndrome!(AGS),!a !type!
1!interferonopathy!which!resembl es!congenital!cytome galovirus!infection!and!is!caused!
.CC-BY-NC-ND 4.0 International licenseperpetuity. It is made available under a
preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
The copyright holder for thisthis version posted January 21, 2021. ; https://doi.org/10.1101/2021.01.21.427598doi: bioRxiv preprint

by!mutation!in!several!genes!encoding!enzymes!responsible!for!nucleic!acid!metabolism!
(Crow!et!al.!2015).!Mutations!in!some!of!these! genes,!such! as!TREX1,!MDA5! and!ADAR1!
trigger!aberrant!presence!of!various!retroelements!and!the!upregulation!of!an!antiviral!
immune!response!(Ahmad!et!al.!2018 ;!Thomas!et!al.!2017).!Interestingly,!anti-reverse!
transcriptase!therapy!in!AGS!pa tients!can!decrease!the!IFN!response,!highl ighting!the!role!
of! aberrant! presence! of! ERVs! in!triggering!an!immune!response! (G.!Rice!et!al.!2018).!
Increased! expression! of! ERVs! has! been! found! in! brains! of! patient! suffering! from!
neurodegenerative!disea ses! such!as! Motor! Neuron!Disease!(Li! et!al.!2015)!and!multiple!
sclerosis!(Johnston!et!al.!2001;!Mameli!et!al.!2007).!Overexpression!of!a!human!ERV!in!
neurons!was!shown!to!be!neurotoxic,!suggesting!a!p otential!role!of!ERVs!in!t riggering!
neuronal!toxicity!(Li!et!al.!2015).!A!direct!link!to!the!pathology!of!these!disorders!has!yet!
to!be!made,!but!nonetheless!ERVs!appear!as!strong!causal!factors!for!autoimmune!and!
neurological!disorders.!
Although!ERV!enrichment!has!been!detected!in!neurological!pathol ogies,!little!is! known!
about!the!function!of!ERV!in!healthy!tissues.!The!exact!role!of!ERV!in!our!immune!system!
and!brain!pathologies!has!yet!to!be!understood!and!there!is!no!model!system!specifically!
looking! at!ERV!function!&'(%&%).!!Zebrafish! is!already!established!as!a!model!to!study!the!
immune! system,! with! significan t! homology! with ! mammals! in! innat e! and! ada ptive!
immunity! (Trede! e t!al.! 2004;! Renshaw! and!Trede! 2012).! The !genetic! tractability! and!
transparency!of!the!zebrafish! embryos!have!allowed!the!creation!of!transgenic!reporter!
lines,!some!of !which!have!elucidated!the!role!of!immune!cell!behaviour!&'(%&%)!(Renshaw!
et!al.!2006).!The!tractability!of!the!zebrafish!has!already!been!exploited!to!visualise!the!
expression!of!the!human!ERV-9!in!oocytes,!similarly!to!human!expression!(Pi!et!al.!2004).!
In! this! study,! we! used! the! zebrafish! as! a! tractable! in! vivo! model! to! characterise! the!
zebrafish!endogenous!retrovirus!( !"#$%).! We!identified! multiple! !"#$%! family! members,!
including!2!complete!genomes!!"#$%/0!and!!"#$%/1.!Using!the!tractability!of!the!zebrafish!
larvae! we! developed! a! reporter! line! for! !"#$%/0! and! imaged! for! the! first! time! ERV!
activation!in!healt hy!tissues! &'(%&%).!We!showed!that!!"#$%/0!is!expressed!in!the!thymus!
and! in! the! brain.! Colocalisation! analysis! and! single! cell! RNA! sequencing! revealed!
expression! of! !"#$%/0! specifica lly! in! T-cells,! suggesting! a! potential! role! for! ERV! in!
lymphocyte! development.! Brain! exp ression! of! ZFERV! appears! to! include! neuronal!
expression.!This!transgenic!line!can!be!used!as!a!tool!to!further!investigate!the!role!of!
ERVs!in!immunity!and!in!neurological!disorders.!
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.CC-BY-NC-ND 4.0 International licenseperpetuity. It is made available under a
preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
The copyright holder for thisthis version posted January 21, 2021. ; https://doi.org/10.1101/2021.01.21.427598doi: bioRxiv preprint

Results"
"
The"zebrafish"genome"contains"multiple"endogenous"retrovirus"integrations."
The!presence!of!an!ERV!in!zebrafish,!named!!"#$%,!has!been!reported!by!Shen!an d!Steiner!
while!screening!a!thymic!cDNA!library!(Shen!and!Steiner!2004)!(Figure"1A).!We!searched!
for!related!sequences!in!t he!most!recent!reference!zebrafish!genome!(GRCz11,!Tü!strain)!
using!BLASTN!searches,!with!the!original! !"#$%!sequence!as!a!query.!Limiting!ourselves!to!
sequences!flan ked!by!long!terminal!repeats! (LTRs)! on!both!sides,!we!retrieved!8 ! hits!
scattered!in! t he!zebra fish!genome,!but!n ot!t he! exact!!"#$%!sequence,!possibly! because!of!
strain! difference! ( Figure" 1+" Sup." Table" 1).! We! identified! 2 ! sequences! encoding!
apparently!fully!functional!ERVs,!with!91%!and!90%!identity!to!!"#$%,!that!we!respectively!
named !!"#$%/0!and!!"#$%/1!(Figure"1B).!These!t wo!ERVs!encode!almost!identical!proteins!
(95!to!97%!identity! at!the!amino-acid!level).! Their! LTRs! are!also!highly!simil a r!(95%!
identity! at! the! nucleot id e! level),! suggesting! that! t heir! promoters! probably! d rive!
expression!in!similar!cells.!An!additional!6!pseudo!!"#$%!genes!(here!call ed!!"#$%2!-!!"#$%3)!
were!identified!(Figure"1C),! !"#$%2!containing!a! frameshift,!!"#$%4!and! !"#$%5!with!large!
deletions! and! !"#$%6,! !"#$%7! and! !"#$%3! containing! a! large! insertion,! all! resulting! in! a!
degenerated!ERV!genome.!
!
!
Figure" 1.!Multiple" copies"of"zferv" are" present" in" the" zebra fish" genome.! A.! Diagram! of! the!
original!zferv!genome!found!by!Steiner!et!al.!used!as!a!r eference!for!nucleotide!identity!(ID%!nt)!
B.!Diagram! representing! the! two! closest! related! !"#$%! genome! found!in!most!recent!zebrafish!
genome!GRCz11,!name d!zferv1a!and!!"#$%/1.!C.!Diagram!of! 6!pseudo!zferv!genes!with!degenerated!
genome! (dotted! line! represents! insertions).! 5’-LTR:!5’!Long! terminal! repeat,! Rep.:!Repetitive!
element,!gag-pol:!genes!encoding!the!polyprotein!and!reverse!transcriptase,!env:!envelope!gene.!
!
!
!
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preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in
The copyright holder for thisthis version posted January 21, 2021. ; https://doi.org/10.1101/2021.01.21.427598doi: bioRxiv preprint

zferv1a!is"actively"expressed"in"the"brain"and"in"the"thymus.!
!"#$%!expression!was!initially!found!in!the!thymus!at!5!days!post!fertilisation!(dpf)!using!
a!RNA!probe!against!the!envelope!(#'%)!gene!of!the!original!!"#$%!(Shen!and!Steiner!2004).!
To! verify! this! observation,! the! entire! !"#$%/0! genome! was! subcloned! from! a! fosmid!!
provided!by!the!Sanger!Center!and! we!used! this!sequence!to!create!an!&'( 8&-9!hybridisatio n!
(ISH)!RNA!probe!against!the!envelope!gene!(#'%)!of!!"#$%/0.!ISH!p erformed!on!a !time!
course! starting! from! 2! cell-stage! embryos! from! the! '0,$#! strain! con firmed! that! the!
strongest!signal! appeared!at!5dpf!(Figure"2).!At!5dpf,!the!thymus!was!strongly!labelled!
(Figure" 2A-B),! similarly! to! what! was! previously! reported! (Shen! and! Steiner! 2004).!
Individual!labelled!cells!were!visible!around!the!thymus!following!the!branchial!arches!
and!around!the!ear!(Figure"2B).!Additionally,!we!identified!a!clear!signal!of!the!#'%!probe!
in!the!brain!(Figure!2A,!2C)!and!the!spinal!cord!(Figure!2A).!!
!
!
Figure" 2:"Reporter"line"for"zferv1a"recapitulates"endogenous"expression.!A.!Expression!of!the!
envelope! gene!(#'%)!by!&'(8&-9(hybridisation!from!2-cell!stage!until!5dpf.!Black!box!highlighting!
strong!expression!around!the!thymus,!black!arrows!highlighting!brain!and!spinal!cord!expression.!
Scale!bar! 500µm.! B.!Zoomed!image!on! the ! thymus!area,!single!positive!cells! are!visible ! in! the!
vicinity!of! the! thymus! around! the! ear! (white! arrowheads)! and! alongside! the! branchial! arches!
(white!arrows).!Scale!bar!70µm.!C.!Dorsal!view!of!#'%!expression!in!the!brain!at!5dpf.!Scale!bar!
100µm.!!
!
!
zferv1a"reporter"line"recapitulates"endogenous"expression.!
To!follow!the!expression!of!the!zebrafish!endogenous!retrovirus!we!identified!as!!"#$%/0,!
we!took!a!transgenic!approach!ta king!adva ntage!of!the!promoter!activity!of!retroviral!
LTR.!We!used!the!5’!viral!promoter!:-$6!from!!"#$%/0!to!drive!GFP!expres sion!by!Gateway!
recombination!(Figure"3A).!Injected!embryos!showing! expression!in!their!thymus!were!
raised!and!screened!in!adulthood!for!germline!transmission.!We!observed!a!strong!and!
consistent!GFP!expression!in!the!thymus!at!5dpf!in!F1!and!F2!larvae!(Figure"3B)!from!
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