PERSPECTIVE
The eme ging ole o ansc ip ional
egula ion in he oocy e- o-zygo e ansi ion
Paulo Na a o-Cos a
1,2
, Rui Gonc¸alo Ma inhoID
3,4,5
*
1Ins i u o Gulbenkian de Ciência, Oei as, Po ugal, 2Ins i u o de Sau
´de Ambien al, Faculdade de Medicina,
Uni e sidade de Lisboa, Lisboa, Po ugal, 3Cen e o Biomedical Resea ch, Uni e sidade do Alga e, Fa o,
Po ugal, 4Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de
Lisboa, Lisboa, Po ugal, 5iBiMED, Depa amen o de Ciências Me
´dicas, Uni e sidade de A ei o, A ei o,
Po ugal
*[email p o ec ed]
Fe iliza ion ma ks he beginning o a new li e by con e ing wo e minally di e en ia ed
game es in o a single o ipo en zygo e. Cen al o his ansi ion is a complex biological p o-
g am commonly e e ed o as oocy e ac i a ion—an umb ella e m o a se ies o p o ound
changes ha p epa e he e ilized oocy e o o ipo ency [1,2]. These include, among o he s,
he comple ion o meiosis, he o ma ion o he wo p onuclei, and he selec i e ansla ion o
ma e nal RNAs. A ema kable aspec o oocy e ac i a ion is ha i occu s in he absence o
ansc ip ion. No su p isingly, mos o ou knowledge o his p ocess is cen e ed on he pos -
ansc ip ional egula ion o gene exp ession [3]. Ye , a ecen body o e idence has b ough
new ocus on he undamen al impo ance o ansc ip ional egula ion du ing oogenesis as a
p ime o he oocy e- o-zygo e ansi ion [4].
In his issue o PLOS Gene ics, To es-Campana and colleagues [5] p o ide new compelling
da a u he suppo ing he iew ha de eloping emale ge m cells ely on highly speci ic gene
exp ession p og ams o la e sus ain oocy e ac i a ion and he oocy e- o-zygo e ansi ion.
Th ough a emale ge m line-speci ic RNA in e e ence sc een in D osophila melanogas e , he
au ho s iden i ied dis inc ch oma in emodele s equi ed o he assembly o he pa e nal p o-
nucleus a e iliza ion: lysine-speci ic deme hylase 5 [Kdm5; also known in D osophila as li le
imaginal discs (Lid)] and i s in e ac ing pa ne s, Sin3A and his one deace ylase 1 (HDAC1/
Rpd3). In he absence o hese ansc ip ional egula o s, hey obse ed ha e ilized oocy es
ailed o e icien ly emo e p o amines om spe m ch oma in—an essen ial s ep o he subse-
quen me ging o he wo pa en al ch omosome se s in ea ly emb yogenesis. Impo an ly,
Kdm5 was also equi ed o mig a ion o he emale p onucleus, clea ly sugges ing mul iple
unc ional equi emen s o his deme hylase o success ul ka yogamy.
The KDM5 amily o p o eins a e Jumonji C lysine deme hylases ha emo e me hyl
g oups om i-me hyla ed and di-me hyla ed lysine 4 on his one H3 (H3K4) [6]. Al hough
i-me hyla ion o H3K4 (H3K4me3) is unlikely o be a p ima y egula o o gene exp ession
[7,8], his his one ma k is highly en iched a he ansc ip ion s a si e o ac i e genes [9] and
may be an impo an aspec o gene exp ession obus ness. Ye , he ec ui men o Kdm5 o
p omo o s is jus one o he mechanisms h ough which hese p o eins can egula e ansc ip-
ion [10,11]. In ac , Kdm5 can also egula e gene exp ession independen ly o i s deme hylase
ac i i y, h ough i s in e ac ion wi h lysine deace ylases (HDACs) and he nucleosome emod-
eling and deace ylase (NuRD) complex [12,13]. The e o e, Kdm5 can beha e, depending on
he cellula con ex , as a posi i e o nega i e egula o o gene exp ession.
PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1008602 Ma ch 5, 2020 1 / 4
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OPEN ACCESS
Ci a ion: Na a o-Cos a P, Ma inho RG (2020)
The eme ging ole o ansc ip ional egula ion in
he oocy e- o-zygo e ansi ion. PLoS Gene 16(3):
e1008602. h ps://doi.o g/10.1371/jou nal.
pgen.1008602
Edi o : Gio anni Bosco, Geisel School o Medicine
a Da mou h, UNITED STATES
Published: Ma ch 5, 2020
Copy igh : ©2020 Na a o-Cos a, Ma inho. This
is an open access a icle dis ibu ed unde he
e ms o he C ea i e Commons A ibu ion
License, which pe mi s un es ic ed use,
dis ibu ion, and ep oduc ion in any medium,
p o ided he o iginal au ho and sou ce a e
c edi ed.
Funding: Paulo Na a o-Cos a (PNC) and Rui G.
Ma inho (RGM) a e suppo ed by Po uguese
na ional unding h ough Fundac¸ão pa a a Ciência e
a Tecnologia g an s (PNC: PTDC/MEC-AND/30221/
2017; RGM: PTDC/BEX-BID/0395/2014, PTDC/
BIA-BID/28441/2017, and UID/BIM/04773/2013
CBMR 1334). The unde s had no ole in s udy
design, da a collec ion and analysis, decision o
publish, o p epa a ion o he manusc ip .
Compe ing in e es s: The au ho s ha e decla ed
ha no compe ing in e es s exis .
Kdm5 deme hylases a e c ucial o he coo dina ion o gene exp ession p og ams ac oss
di e en de elopmen al con ex s [14]. Mo e ecen ly, hei impo an unc ions du ing oogen-
esis ha e begun o be unco e ed. We and o he s ha e shown ha D osophila Kdm5 es ic s
he le els o H3K4me3 in de eloping emale ge m cells and is equi ed bo h o synap onemal
complex assembly and he empo al con ol o gene exp ession du ing meiosis [15,16]. Such
unc ions highligh he ole o hese enzymes as po en ch oma in emodele s du ing emale
game ogenesis, which is u he illus a ed by he signi ican de ec s in meio ic and pos meio ic
ch omosome a chi ec u e obse ed in Kdm5-deple ed oocy es [15,16]. No su p isingly, he
loss o Kdm5 and i s deme hylase ac i i y a e associa ed wi h a signi ican educ ion o emale
e ili y [15].
Now To es-Campana and colleagues [5] u he expand he gamu o Kdm5- ela ed unc-
ions du ing oogenesis o include he ansc ip ional egula ion o deadhead (dhd)—a majo
playe in he oocy e- o-zygo e ansi ion. dhd encodes a hio edoxin-like p o ein ha was p e-
iously desc ibed o be essen ial o spe m ch oma in decompac ion a e e iliza ion [17].
The au ho s obse ed ha dhd exp ession was se e ely educed in Kdm5-deple ed oocy es [5],
which is in acco dance wi h hei eco ded incapabili y o o ming he pa e nal p onucleus.
Impo an ly, Kdm5 deple ion was associa ed wi h a sha p dec ease o H3K4me3 ac oss he
dhd gene body, sugges ing ha Kdm5 di ec ly egula es dhd exp ession. Al hough his coun-
e in ui i e loss o H3K4me3 a e deple ion o a his one deme hylase would a o a deme hy-
lase-independen unc ion o Kdm5, his does no seem o be he case. In ac , in a a he
su p ising wis o e en s, a deme hylase-inac i e allele o Kdm5 ailed o escue dhd exp es-
sion le els in Kdm5-deple ed oocy es.
How can we econcile he seemingly con adic o y obse a ions ha Kdm5 deme hylase
ac i i y is equi ed o dhd exp ession bu he absence o Kdm5 is in i sel associa ed wi h low
le els o H3K4me3 in dhd? Two nonmu ually exclusi e hypo heses can be en isaged. In he
i s , Kdm5 egula es H3K4me3 le els in a ye unknown enhance sequence esponsible o he
con ol o dhd exp ession. In he second, a speci ic Kdm5-media ed o ganiza ion o ge m-cell
ch oma in a chi ec u e may be equi ed o he e icien exp ession o dhd. Unde his hypo h-
esis, we can posi a scena io whe e Kdm5 deple ion impai s he o ganiza ion o opologically
associa ing domains (TADs) due o inc eased H3K4me3 and/o educed ac i i y o Kdm5-in-
e ac ing pa ne s (such as he SIN3 his one deace ylase complex).
An impo an poin om To es-Campana and colleagues’ s udy [5] ega ds he expe i-
men in which he au ho s a emp o supp ess, ia ec opic exp ession o dhd, he spe m ch o-
ma in- emodeling de ec s o Kdm5-deple ed oocy es. The ou come o his expe imen was a
qui e modes deg ee o unc ional escue, which clea ly sugges s ha besides dhd, Kdm5 egu-
la es he exp ession o o he genes simila ly impo an o pos e iliza ion de elopmen . Such
obse a ion pa allels ou p e ious esul s on he mixed-lineage leukemia 3/4 (MLL3/4) his one
me hyl ans e ase [known in D osophila as dMLL3/4 o i ho ax- ela ed (T )], in which we
could demons a e ha he ac i i y o his ch oma in emodele du ing oogenesis p omo ed
he exp ession o a subse o genes la e equi ed o di e en aspec s o he oocy e- o-zygo e
ansi ion [4]. Qui e signi ican ly, he loss o his me hyl ans e ase was associa ed wi h a
b oad pale e o oocy e ac i a ion de ec s, such as he incapabili y o comple ing meiosis, o m-
ing he pa e nal p onucleus, and ini ia ing he emb yonic mi o ic di isions.
Collec i ely, hese s udies emphasize he poin ha ansc ip ional egula ion du ing
oogenesis p epa es he oocy e o ac i a ion (Fig 1). We can hus hypo hesize ha di e en
epigene ically de ined gene exp ession modules es ablish, as he oocy e de elops, he molecula
basis o he u u e oocy e- o-zygo e ansi ion. In his ega d, i is impo an o men ion ha
he dis up ion o his one deme hylases du ing mouse oogenesis [including lysine-speci ic
deme hylase 5B (Kdm5b)] has also been associa ed wi h meio ic de ec s and emale in e ili y
PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1008602 Ma ch 5, 2020 2 / 4
[18]. I is he e o e likely ha some o he key molecula playe s esponsible o o ches a ing
oocy e ma u a ion and he oocy e- o-zygo e ansi ion a e e olu iona ily conse ed be ween
D osophila and mammals. Acco dingly, explo ing he ole o ch oma in- emodeling enzymes
such as Kdm5 in he con ex o human e ili y ep esen s an exci ing and s ill clinically unde -
explo ed opic.
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