Turning X chromosome ‘off and on again’ critical for oocyte development

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. To address this question, researchers at 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.

“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.

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