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New sperm poised to become any cell
In the body, a skin cell will always be skin, and a heart cell will always be heart. But in the first hours of life, cells in the new embryo become totipotent — they have the incredible flexibility to mature into skin, heart, gut, or any type of cell at all.
It was long assumed that the joining of egg and sperm launched a dramatic change in how and which genes were turned on. Instead, new research shows that totipotency is a process beginning as early as the adult germline stem cells (AGSCs) which reside in the testes and are precursors to sperm.
The study was co-led by Bradley Cairns, PhD, University of Utah professor of oncological sciences and Huntsman Cancer Institute investigator, and Ernesto Guccione, PhD, from the Agency for Science Technology and Research in Singapore. They worked closely with Saher Sue Hammond, PhD and first author. Their research was published online in the journal Cell Stem Cell.
Typically, sperm precursor cells live a mundane life. They divide, make more cells like themselves, then receive a signal to mature into sperm.
New evidence, however, suggests these cells have the potential to do more.
Under conditions that promote them to form into testicular teratomas - dense cancerous masses - these young sperm transform into precursor cells for skin, muscle and gut.
This observation prompted investigators to examine the genes programming sperm precursor cells. How could gene programming change a cell destined to become one single cell type into becomming a cell with the potential to become anything?
The answer is that sperm precursor cells are somewhere in between.
The strongest evidence comes from a quartet of genes: Lefty, Sox2, Nanog, and Prdm14. When activated, these genes can trigger a cascade of events giving cells stem cell properties. In cells limited to becoming one cell type, these genes are turned off.
In sperm precursor cells, Lefty, Sox2, Nanog, and Prdm14 genes wear a code of chemical tags - called methylation groups - indicating in sperm precursor cells they may be silenced, but they are poised to become active. In other words, embedded within sperm precursor cells is the potential to become totipotent cells capable of becomming anything the body needs.
Cairns compares the tags on the poised genes to bookmarks. Once fertilization occurs, sperm precursor cells can quickly become fully totipotent.
“Sperm cells and their precursors put ‘bookmarks’ on all the important genes they need to access quickly. Then, when the sperm and egg come together, all they have to do is complete the job already started.”
Bradley Cairns, PhD, professor of oncological sciences, University of Utah, and Huntsman Cancer Institute investigator,
This engineering feat, Cairns believes, ensures that when needed a transition occurs rapidly and accurately. The result is just one of many that make up a detailed playbook documenting genetic and epigenetic changes taking place along the way to cellular function.
Future studies will continue to provide a deeper understanding of the molecular cascades that govern totipotency, cancer, and fertilization.
•Self-renewing (Thy1+) versus differentiating (Kit+) germline stem cells are profiled
•Thy1+ to Kit+ comparisons reveal major differences in signaling and transcription
•Promoters and enhancers for pluripotency genes are “poised” by chromatin
•Gametogenesis involves transcription with DNA methylation at many promoters
Adult germline stem cells (AGSCs) self-renew (Thy1+ enriched) or commit to gametogenesis (Kit+ enriched). To better understand how chromatin regulates AGSC biology and gametogenesis, we derived stage-specific high-resolution profiles of DNA methylation, 5hmC, histone modifications/variants, and RNA-seq in AGSCs and during spermatogenesis. First, we define striking signaling and transcriptional differences between AGSC types, involving key self-renewal and proliferation pathways. Second, key pluripotency factors (e.g., Nanog) are silent in AGSCs and bear particular chromatin/DNAme attributes that may “poise” them for reactivation after fertilization. Third, AGSCs display chromatin “poising/bivalency” of enhancers and promoters for embryonic transcription factors. Remarkably, gametogenesis occurs without significant changes in DNAme and instead involves transcription of DNA-methylated promoters bearing high RNAPol2, H3K9ac, H3K4me3, low CG content, and (often) 5hmC. Furthermore, key findings were confirmed in human sperm. Here, we reveal AGSC signaling asymmetries and chromatin/DNAme strategies in AGSCs to poise key transcription factors and to activate DNA-methylated promoters during gametogenesis.
About Huntsman Cancer Institute at the University of Utah
Huntsman Cancer Institute (HCI) is one of the world’s top academic research and cancer treatment centers. HCI manages the Utah Population Database - the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer, and paraganglioma. HCI is a member of the National Comprehensive Cancer Network (a 25-member alliance of the world's leading cancer centers) and is a National Cancer Institute-Designated Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.
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