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A molecular alarm clock wakes resting eggs

At the start of reproductive life an ovary contains, on average, several thousand immature eggs (ovules) in a resting state — that can last for decades. But how does each resting egg know at what time to prepare for ovulation?

Published in the latest issue of Nature Communications, researchers at Instituto Gulbenkian de Ciencia (IGC) and at the University of Algarve — both in Portugal, along with researchers at the University at Albany (USA), have discovered that in the fruit fly a molecular "alarm clock" tells resting ovules the right time to wake up. Defects in this alarm clock result in female fertility problems.

Cells divide and reproduce in two ways: mitosis and meiosis:
• Mitosis is cell division which results in two identical daughter cells.
• Meiosis is cell division which reduces the chromosome number by half in each of two divisions of the nucleus, resulting in four gametes (sex cells). Each of the four resulting cells, therefore, has half the number of chromosomes of the original cell.

Mitosis leads to the growth of tissues, fibers, and membranes.
Meiosis leads to cells for sexual reproduction of that organism.

Ovules rest in the ovary. After the prophase 1 stage of their first meiotic division, their chromosomes remain tightly coiled in a state of "hibernation" as genes cannot be read and transcribed to initiate changes to ovule structure. When the chromosomes are unwound, genes are then able to be "read" — effectively genes are turned back on.

Led by Rui Martinho, researchers observed that a deviation in an egg’s maturation can be brought on in early formation by removing the dKDM5 histone. Histones are enzymes that uncoil the tightly wound chromosome, allowing for "reading" of the genes on the DNA coil. Researchers, therefore, found that late prophase I programming of an ovule's epigenome affects its' subsequent function, or how an ovule "turns genes back on".

"Similar to humans, fruit fly ovules have a resting period during meiosis. Therefore, they could help us understand exactly how an ovule is able to turn back on its genes at the right time, a biological mystery until now."

Paulo Navarro-Costa PhD, Departamento de Ciências Biomédicas e Medicina, and Center for Biomedical Research, Universidade do Algarve, Campus de Gambelas, and the Instituto Gulbenkian de Ciência, Portugal, and first co-author of this study.

Research had found that ovules keep track of time similar to a molecular "alarm clock" via the protein dKDM5 which produces the histone dKDM5.  Rui Martinho explains: "When ovules begin to form, the dKDM5 histone modifies their chromosomes so they will only activate genes at a specific time. If this "alarm clock" is incorrectly set due to defects in the dKDM5 protein, females become infertile as their ovules fail to complete meiosis."

An unexpected property of this new molecular alarm clock is that it is set at early stages of egg formation, long before the cell needs to be awakened.

"We observed that perturbation of the oocyte’s epigenome in early oogenesis, through depletion of the dKDM5 histone demethylase, results in the temporal deregulation of meiotic transcription and affects female fertility.(abstract)

"These results illustrate just how important the early life of the ovule is to female fertility. For instance, the early stages of ovule formation occur before women are born, while they are still in their mother's womb. Prenatal development is critical for the future formation of healthy reproductive cells."

Paulo Navarro-Costa.

Oocytes are arrested for long periods of time in the prophase of the first meiotic division (prophase I). As chromosome condensation poses significant constraints to gene expression, the mechanisms regulating transcriptional activity in the prophase I-arrested oocyte are still not entirely understood. We hypothesized that gene expression during the prophase I arrest is primarily epigenetically regulated. Here we comprehensively define the Drosophila female germ line epigenome throughout oogenesis and show that the oocyte has a unique, dynamic and remarkably diversified epigenome characterized by the presence of both euchromatic and heterochromatic marks. We observed that the perturbation of the oocyte’s epigenome in early oogenesis, through depletion of the dKDM5 histone demethylase, results in the temporal deregulation of meiotic transcription and affects female fertility. Taken together, our results indicate that the early programming of the oocyte epigenome primes meiotic chromatin for subsequent functions in late prophase I.

This study was conducted at Instituto Gulbenkian de Ciência and at University at Albany, and was funded by Fundação para a Ciência e a Tecnologia (Portugal), and the National Institutes of Health (USA).

*Paulo Navarro-Costa, Alicia McCarthy, Pedro Prudêncio, Christina Greer, Leonardo G. Guilgur, Jörg D. Becker, Julie Secombe, Prashanth Rangan and Rui G. Martinho. (2016) "Early programming of the oocyte epigenome temporally controls late prophase I transcription and chromatin remodeling", Nature Communications. DOI: 10.1038/NCOMMS12331
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Aug 25, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Ovarian follicle of a fruit fly (ABOVE):
Chromosomes stained GREEN
dKDM5 protein stained RED.
Image Credit: Paulo Navarro-Costa, IGC.



Phospholid by Wikipedia