(Boston)—The global birthrate has been in significant decline for decades. In the U.S., couples are deciding to have children later in life. A 2022 U.S. Census data analysis of Census Bureau and National Center for Health Statistics data, reveals that fertility rates for women age 20-24 declined by 43% during the period from 1990 to 2013. But the numbers of women age 35-39 giving birth increased by 67%, and for women between 40- 44 that increase was nearly 139%.
Women who decide to have children in middle age depend on sperm and egg resiliency. Part of germ cell (also known as egg cells and sperm cells) resilience depends on a functional piRNA pathway to protect germ cell genomes decades after puberty, which is when in humans, the Piwi pathway is activated as well as the expression of transposon RNAs—mobile DNA sequences that can move around a genome.
Researchers from Boston University Chobanian & Avedisian School of Medicine have found a new role for the transcription factor (proteins that regulate the transcription, or copying, of genes). In the fruit fly, this transcription factor, named Traffic Jam, activates a non-coding piRNA gene named Flamenco to promote female fruit fly (drosophila) fertility. The discovery solves the 30-year-old mystery of how Flamenco gets activated to protect fruit fly ovaries from a series of genetic parasites called retroviral transposons, and may one day help with infertility issues in humans.
"The discovery of Traffic Jam's function in flies will help us look into humans with infertility symptoms and see if those patients lacking functional sperm may have defects in these Piwi genes and transcription factors," explains corresponding author Nelson Lau, PhD, associate professor of biochemistry and director of the BU Genome Science Institute.
Lau and his colleagues first conducted a series of luciferase-reporter assays that measure gene activity and biological responses in 2017, discovering important new regulatory sequences in the Flamenco locus. They confirmed the biological importance of those Flamenco DNA sequences by generating new fruit fly mutants with CRISPR genome editing. They then carried out proteomics experiments and made the first discovery of Traffic Jam binding to Flamenco DNA sequences. Lastly, they conducted RNA interference knockdowns and chromatin immunoprecipitation sequencing studies of Traffic Jam in fruit fly ovary cells to confirm this new genetic interaction.
They found that Traffic Jam driving the production of Flamenco piRNAs bound by Piwi proteins, allowed fruit flies to protect their germline genome and produce fertile eggs and offspring. They also found that the retroviral transposons are also activated by Traffic Jam, hijacking this host factor. This finding is surprising because it demonstrates the on-going war between the animal's genetic immune system and the genetic parasites fighting for their own survival.
According to the researchers, this study investigates the fundamental battle for the protection of germline genomes that humans depend on for fertility and reproduction. "We humans are like fruit flies in that our gonads also generate piRNAs to protect our germ cells against transposons. We have our own version of the Traffic Jam gene, called MAF-B, which we can test in future studies to see if MAF-B regulated human piRNA genes to allow us to produce functional sperm," adds Lau.
These findings appear online in the journal Cell Reports. Lau's team also contributed to an accompanying study in the same issue of Cell Reports by researchers in France and the United Kingdom.
N.C.L. is funded by NIH/NIGMS (grants R01GM135215 and equipment supplements), and a grant from the Boston University Institute of Sexual Medicine contributing support to R.K.G. and J.Z.
