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The decline in global birthrates has become a notable trend over the past several decades. In the United States, many couples are opting to delay starting families. An analysis of 2022 U.S. Census data indicates a remarkable 43% drop in fertility rates among women aged 20-24 from 1990 to 2013. Conversely, the birthrate among women aged 35-39 surged by 67%, with an astonishing increase of nearly 139% for those aged 40-44.
The decision for women to have children later in life raises important considerations regarding the viability of sperm and egg cells as they age. A crucial factor contributing to the resilience of these germ cells is a functional piRNA pathway. This pathway serves to safeguard the genomes of germ cells long after puberty, when the Piwi pathway becomes activated, accompanied by the expression of transposon RNAs— DNA sequences capable of relocating within a genome.
Researchers at the Boston University Chobanian & Avedisian School of Medicine have unveiled a novel function of a transcription factor—proteins that manage the transcription process of genes. This transcription factor, termed Traffic Jam, is responsible for activating a non-coding piRNA gene known as Flamenco, which plays a pivotal role in enhancing fertility in female fruit flies (Drosophila). This breakthrough addresses a 30-year-old question regarding the activation mechanism of Flamenco and its function in protecting fruit fly ovaries against genetic parasites known as retroviral transposons. The implications of this research could extend to addressing infertility challenges in humans.
“Understanding Traffic Jam’s role in fruit flies will allow us to explore infertility in humans and determine if individuals with non-functional sperm possess defects in Piwi genes and related transcription factors,” noted Nelson Lau, PhD, the corresponding author and associate professor of biochemistry at the BU Genome Science Institute.
In their research, Lau and his team conducted luciferase-reporter assays to assess gene activity and biological responses, discovering crucial regulatory sequences within the Flamenco locus in 2017. They verified the significance of these Flamenco DNA sequences by developing new fruit fly mutants through CRISPR genome editing techniques. The team subsequently performed proteomics experiments, leading to the first detection of Traffic Jam’s binding to Flamenco DNA. They further validated this genetic interaction through RNA interference knockdowns and chromatin immunoprecipitation sequencing within fruit fly ovary cells.
The researchers determined that Traffic Jam facilitates the production of Flamenco piRNAs, which are then bound by Piwi proteins, allowing fruit flies to safeguard their germline genome and produce viable eggs and offspring. Interestingly, the retroviral transposons were also found to be activated by Traffic Jam, essentially exploiting this host factor. This unexpected outcome reveals an ongoing struggle between the genetic defense mechanisms of the host and the survival tactics of genetic parasites.
The study highlights the essential conflict over the preservation of germline genomes, which are vital for human fertility and reproduction. “Similar to fruit flies, humans also generate piRNAs in our gonads to protect our germ cells from transposons. We possess a human counterpart to the Traffic Jam gene, MAF-B, which we intend to investigate in future research for its role in regulating piRNA genes that contribute to the production of functional sperm,” Lau explained.
The significant findings of this research were published in the journal Cell Reports, where Lau’s team also contributed to a joint study alongside researchers in France and the United Kingdom.
N.C.L. received funding from NIH/NIGMS (grants R01GM135215 and equipment supplements), as well as a grant from the Boston University Institute of Sexual Medicine, which supported R.K.G. and J.Z.
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