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P E O P L E I D E A SJane Skok: Choreography of allelic exclusionAf te r adecade-long hiatus from science, Jane Skok retu rnedto the labto study the mechanism th at al lows each B celttosecrete antibodies th atrecognize only one target.

I didn't wanttobedoingfor therestof my l i fe;I wantedit tohave somemeaning.

Antibody divenityis generated duringB cell development by therearrange-mentofvariable (V), diversity (D),andjoini ng (J) segnients of immu noglobulin(Ig) genes. Both alelesofeachIglocuscan initiate rearrangement, b ut only onealele successfully rearranges. As soonasthis occurs, the other aleleispreventedfrom following suit. This mechanism,knownas allelicexclusion,guarantees that eachBcell produces antibodiesspecific for just onean-tigen.In herlaboratoryat NewYork Univer-sity (NY U), Jane Skokstudies how exclusionis established.

Skok's initial forayinto research involveddissecting the genetics ofthe complement cascade with EllenSolomon at Cancer Research UK (1).But immediately after earning her Ph.D.,Skok left science to care for her ill child.Wh en she returned nearlyadecade later,she had to start from scratch. Alter gettingup to speed with a Master's in im mu nol-ogy, shejoin ed Ajnanda Fisher'slab,where she gravitated toward B cells andthe question of aUelic exclusion.Skokhassince helped define som eofthe steps that make exclusion possible.She discovered that the excludedIgaUele gets sentto repressive DNAdo-mains near the centromere, whereas theproductive alele remains within accessi-ble domains (2-4). She later focusedonone of the m ore curious aspects of allelicexclusion. Du ring rearrangement, theIglocus contracts, allowing V. D, andJsegmentsto getcloseto each other andjoin up. Skok found thatthe successfulrearrangement ofonealele triggers locusrelaxation, thereby stopping rearrange-mentofthe othe r alele (5). Sheisno whunting for theproteinsandpathwaysthat direct the contortion andmove-mentofIg loci.

A PROMISING STARTWhat inspired youtobecome scientist?Thereare amixtureofartistsand sci-entists in my family, and enjoyed bothdisciplines.But solving problemswasmuch more satisfyingtome, soIchosescience.Tellmeabout your graduate egreein

geneticsI worked on the genetics of the firstcomponentofthe com plement system,Clq, in Ellen Solomon's lab.We showedthatClq isencodedby distinct setsofgenesin fibroblasts and serum.This wasmy first paper, which I publishedin arelatively short timein i\if(rc.This gaveme an unrealistic outlook of whatIwould face in thefiature.1reniemberthink ing, "O h, wow. this is so easy."What happened then?My second childgotsick. It's very hardto work when you have young children.But when you've goti sick childandyou're in and out of hospitals all thetime,its almost impossible. I managedtofinish my Ph.D ., butI stopped after thatfor almost ten years.A PROLONGED STOPIVltat did you do during that time?I took care of my child until slit- got bette rand then had two more children.I en-joyed being with mychildren but wasbored without the challenge ofacareer.I've always enjoyed art, so wentto artschool. Although that wasagoodex-perience,it wasn't very challenging.Imissed havingthepressureofa focusedjob.SoIdecidedtogo backtoscience.Wliat didthekids think about thatdecision?I don't think the older ones mindedbecause they were growing up anddidn't needme asmuch.I went backsoon after myyoungest daughterwasborn. She was too youngto know any

ane Skok

betterandhadn't begun to talk yetso she couldn't tellmeanything.What wasit liketoreturntoscience afterten years?I hadn't keptupwiththeliterature andhad forgotten a lot of what I had learned.I decided tostartbydoinga Master'sdegree, thinking thatitwould beagoodwayoflearning and getting orientediwhatever fieldIwas goingto gointo.decided to study immunology becauseI'd had some exposureto itwhen I waworking on ClqinEllen's lab.

But it was a tough beginning becauseimmunologyis not the easiest subjectgo into. I was reading like crazy to makesemeofit all. But betw een the ch ildrenand the studying, it was pretty hard going.It was also quitea challenge making mybrain work after ten years.I hadzeroconfidence at that pointandfelt thatwasn't going to makeit.Wiiat made you keep going?The thought t iatifididn't get back intoit,I'd bestandingin thesame placeianother ten years' time. That wasa scarthought because I didn't want to bdoing nothingfor therestofmy life;wantedit tohave some m eaning.

During myM aster's, I did a shonresearch project with David Gray,whwasa great mentor. He's one of thosepeoplewho can see thepointofsomething very clearly w ithout getting bogged1 5 1 4 JEMVOL205, No. 7,2006

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Textand Interview byHema Bashyamhbashyam@rockefel ler.edu

Large pre-B Small pre-B SplenicBcell

In developingcells, only the excluded alele red andgreen) ispositionedatrepressivecentromeric domains (blue).down inlotsofinfonnadona problemthat I was experiencing.Healso educatediiiL' .ihoiit Rinding oppominities and sup-ported me in applying tor a WellcomeTrust Career Reentry Award, which is agrant that enables you to get back into sci-ence artcr taking a break. Idoti'c knowifthere's an equivalent liinding programhereinthe US, butitprovides a very goodopportunity forpeople who've had a ca-reer breaktoget backinthe game.In theUK, mostly women applyfor it.WlienIlatermetsomeofthose women, Ifoundout that we had all iced the same problemgoing backtoscience: lack of confidence.BACK ON TRACKlilial did you tvorkonwhen you {ofhacklofhe Iah?1 started towork inDavidslab on howcytokines producedby Bcells influencethe differentiation of T cells. Withinayear of getting my funding, he movedtoEdinburgh,butluckily,bythat time,wehad enough datatopublishapaper.Was David smoveaseihackfor you?N o,itactually ended upworking in myfiivor.This is how collaborations and inter-disciplinary science comes bibout. MandyFisher, who wasin thenext building, waslooking at thepositioning ofIkaros inresting versus activatedBcells. I was help-ing herpurify thecells,andwhen sheheard Davidwa leaving, she offered me a

position in her lab tolook atwhere Iggenes were positionedinthe nucleus. SoIwas doing new tilings again and was backin theland C3 "Don' t know anytbnig."WJiatwasyourexperieitce iuMa udy s lab?Like David, Mandy is a clear-thinkingperson whohelped mefocus. Although1 was backtosquare one againandread-ing papersandtextbooks,Imanaged toget things working. I showed that oneoftheIgalelesisrepositioned atrepressivepericentromeric domains in activatedmatureBcellsandthat thisisimportantfor maintaining expression ofonlyonealele.Atthe end ofmy timeinMandy'slabIsuccessfully applied fora WellcomeTrust University award, which camewith tenureatUCL.

WhileIwasinMandy's lab.1got towork with Steven Kosak.Hehad shownchat g loci are initially locatedatthe cellperiphery innon-B cellsbuttbencon-tract andmove toward thecenter in Bcells. In collaboration with Stevenandalso Harinder Singh. I did 3D FISHexperiments tovisualizethelocalizationof Igloci in Bcells.W efound thatIggenes move in from theperipberv'asthey undergo rearrangement and thatthey contract as they move.Hou is this contraction regulated?This waswork I did in collaborationwith Meinrad Busslinger in Vienna, who

I always wto knowtheanswerto next questiandIwantto knowityesterday.

had askedme ifI'dbeinterested indoingsome FISH experiments to look at theIgH locus in Bcells lacknig the tran-scription factor Pax5. That's when Idiscovered that Pax5 is necessary forlocus contracrionoftbe lgheavy chain.Backin my ownlab,wesoon foundtbat the Ig locus decontracts as soon as theheavy cbain bas finishedrearranging. We then wenton to sbow tbat contrac-tion also occursat tbe lgkappa (light cbain) locusduring recombination, andtb;it one alele is reposi-tioned atbeterocbromaticdomains before rearrange-ment occurs, wbicb is theopposite ofwbat bappenswitb tbe heav\' cbain locus.Tbis work was doneincollaboration withYebudit Bergman and later with MaijorieShapiroandSean Fitzsimmons.THE NEXT STEPSIf bothaleles contractand can riromhine,what prevents simultaneous rearrangementofboth aleles?That's a fantastic question tbat we're work-ingon at tbenionieiit.Tbe fact tbat onlyone alele gets functionally rearrangedimplies tbat there'samechanismfor pre-venting simultaneous rearrangement onbotb aleles. Fred Alt first proposed thisidea backin1992.We are trying to under-stand bow thepositioning of the twoaleles regulates this and to determinewbat roletberecombinase enzymes play.Sounds like youW };otenou h ouyourplate to stay busy for a while.I think it'sgood to have a long-termproject becauseitreally gets you focusedon something. I didn't reallygethookedinto science until 1gothooked into thisproject. I amvery impatient aboutget-ting data because1always want toknowtbe answer to tbe next question,and Iwanttoknow ityesterday.1. Skok,J..et al.1981.,V,ifHrc. 292:549-551.2. Skok,J.A..etal.2()0I.\',ii. himtinol.2:S48-S54.3. Kosak.S.T,eiai.2L)()2.,VimY. 296:158-362.4. Fuxa,M..etal.20tH.GCTJcsD'. 18:411-422.5. Roldm . E.,ct;i .2IMI5.Wu.nimimoi (r.M-4\.

PEOPLEft IDEASIThe JournalofExperimental Medicine 1S1B

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