Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have
identified a potential new diagnostic marker that predicts the successful
and efficient development of mammalian egg cells. The findings could pave
the way for generating artificial oocytes in the laboratory, helping
researchers study the causes and treatments of infertility disorders and
test the impact of drugs and chemicals on women’s reproduction. The research
is published in The EMBO Journal.
Humans have 23 pairs of chromosomes. Between males and females, 22 pairs are
shared, with the 23rd pair being the sex chromosomes. Males usually have an
X and a Y chromosome, while females have two X’s. This presents a potential
problem for the female cellular machinery, as two active X chromosomes
generates an overdose of gene products, which is fatal for developing
embryos or leads to cancer in adult life. To avoid this scenario, female
cells inactivate one X chromosome by turning off its genes and compacting
it.
Little is known about how X-chromosome inactivation affects the development
of reproductive cells. In mammals, oocytes develop from germ cells,
precursor cells that migrate from early embryonic tissue to the developing
gonads. Germ cells then undergo meiosis, an important chromosomal
rearrangement process, which is responsible for the genetic uniqueness of
each individual germ cell. Germ cells mature and eventually turn into
functional sperm or oocytes.
To address this question, researchers at the Centre for Genomic Regulation
(CRG) built an X-chromosome reporter system (XRep), a tool which allowed
them to study how the chromosome shapeshifts over time during germ cell
development in vitro.
Using female mouse cells, the method revealed a carefully orchestrated act
of X-chromosome ‘yoyo’. If one X chromosome briefly inactivated and then
reactivated, it resulted in germ cells being four times more efficient for
entering meiosis and transforming into egg cells compared to germ cells that
have never turned their X chromosome ‘off and on’ again. In comparison, germ
cells that failed to inactivate the X chromosome in the first place or
reactivated it too rapidly showed abnormal gene expression and cell
differentiation patterns.
The study also found that cells with two active X chromosomes divided faster
and easily reverted into a state of pluripotency. According to the authors,
these characteristics are similar to human germ cell tumors, which come form
germ cells that got lost during their migration to the gonads or failed to
differentiate properly once inside the testicles and ovaries. The
researchers deduced that a correct X-chromosome inactivation and
reactivation sequence is an indicator of normal germ cell differentiation.
The research team notes that further studies will be needed to confirm
whether an abnormal X-chromosome state is a diagnostic indicator, or whether
it could be a causal factor responsible for the cell abnormality.
“Our findings have important implications for reproductive research because
XRep allows us to assess cellular X-chromosome status in real time, helping
identify and isolate germ cells with a high success rate of turning into
oocytes,” says Dr. Bernhard Payer, Group Leader at the CRG and senior author
of the study.
“Human oocytes have never been generated completely in vitro. Monitoring the
X-chromosome state during in vitro germ cell differentiation might therefore
be a way to optimize the protocol to produce high quality human eggs in the
lab. Human eggs for research are scarce and difficult to obtain because they
are currently only available from egg donors and mostly used for
reproductive purposes. In vitro-generated human eggs could therefore provide
an unlimited resource to study the causes and treatments of infertility
disorders and as well to test the safety of drugs and chemicals for women’s
reproduction”, concludes Dr. Payer.
Dr. Moritz Bauer, co-first author of the study, adds: “Our results also
highlight how we need specific tools to study female cells. The vast
majority of studies are performed using male cells, leading to a gender-gap
in scientific knowledge. We therefore need to stop looking at female
development through the lens of male cells, which will contribute to our
understanding of sex-specific disease progressions.”
Reference:
Jacqueline Severino, Moritz Bauer, et al. Controlled X-chromosome
dynamics defines meiotic potential of female mouse in vitro germ cells, The
EMBO Journal (2022)e109457 DOI: 10.15252/embj.2021109457