During the development of the skin, a transcription factor called SOX9 directs stem cells to evolve into either epidermal cells or hair follicle cells. If mismanaged, this process can lead to specific cancers. A study conducted by Rockefeller scientists has found that SOX9 is part of an exclusive group of proteins known as “pioneer factors,” which have the ability to unlock and activate formerly dormant genes, providing fresh perspectives on cancer growth and new potential treatments.
In initial phases of development, every stem cell faces a crucial choice. For instance, in skin development, embryonic epidermis begins with a single layer of epidermal precursor cells, which must choose to mature into epidermal cells or develop into hair follicle cells. This vital decision, regulated by SOX9, results in hair follicle cell growth when SOX9 is present in the precursor cell, or epidermal cell development when it’s absent.
However, SOX9 also has a dangerous aspect, as it’s linked to some of the most deadly cancers worldwide, such as those of the lung, skin, head, neck, and bone. Within the skin’s context, certain irregular adult epidermal stem cells might inadvertently activate SOX9, regardless of their chosen path, and fail to deactivate it, initiating a process that ultimately triggers cancer genes.
The exact molecular process leading to this fatal consequence has remained obscure. But Rockefeller researchers have now exposed the mechanics of this harmful transformation. They have determined that SOX9 is part of a specific protein category that oversees the transfer of genetic information from DNA to mRNA. This allows SOX9 to access and bind to previously inaccessible genetic material, activating dormant genes. The findings were published in Nature Cell Biology.
According to Elaine Fuchs, leader of the Robin Chemers Neustein Laboratory, this discovery provides fresh insights into how cancer disrupts stem cell decision-making, making it impossible for them to form normal tissue. It also highlights new genes activated by SOX9 as possible therapeutic targets.
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Uncommon Keys to Gene Expression
Our genome isn’t readily accessible; rather, it’s akin to a library filled with billions of locked books, with the majority of genetic material lying dormant within bound packets of DNA. These genes, locked within what’s termed closed chromatin, are unreachable to transcription proteins that would enable gene expression.
However, some rare “pioneer factors” like SOX9 can unlock these genetic packets, having the unique ability to access closed chromatin and activate new genes.
This generally occurs during early development, where a stem cell’s destiny is undecided. In adult skin, SOX9 usually maintains adult hair follicle stem cells’ identity and is usually suppressed in adult epidermal stem cells. But this is not the case for certain carcinomas.
The researchers discovered the step-by-step process by which SOX9 gets reactivated in adult epidermal stem cells. They engineered mice to activate SOX9 in their adult epidermal stem cells, progressively reprogramming them. This led to the induction of carcinoma-like structures and eventually human-like basal cell carcinoma.
They also tracked the epigenetic process happening concurrently, where SOX9 switched off epidermal stem cell genes and activated hair follicle stem cell genes. They found that SOX9 seized the nuclear machinery from active epidermal genes to turn on the silent hair follicle genes.
“When SOX9 was unregulated, the stem cells failed to produce hair but kept proliferating, leading to a basal cell carcinoma state,” says Fuchs.
This complex identity shift was made possible due to SOX9 being a pioneer factor, as only a pioneer factor can access closed chromatin.
Since SOX9 is hyperactive in many lethal cancers, researchers plan to explore ways to interfere with its role in these cell proliferations. “By recognizing how SOX9’s interacting proteins and target genes change during malignancy, we hope to find new drug targets for these cancers,” Fuchs adds.
Reference: Yihao Yang et al., “The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates,” Nature Cell Biology, 24 July 2023, DOI: 10.1038/s41556-023-01184-y.
Frequently Asked Questions (FAQs) about
What is the transcription factor SOX9 and why is it significant?
SOX9 is a transcription factor that guides stem cells to become epidermal cells or hair follicle cells. It belongs to a special class of proteins known as “pioneer factors,” capable of opening sealed pockets of genetic material and activating previously silent genes. Its significance lies in its association with some of the most lethal cancers worldwide, such as lung, skin, head and neck, and bone cancer. Researchers have discovered how SOX9’s misregulation can activate cancer genes, providing new insights into cancer development and potential therapeutic targets.
How does SOX9 contribute to the development of certain cancers?
SOX9 can contribute to cancer development when misregulated. In certain aberrant adult epidermal stem cells, SOX9 might be unexpectedly activated and never turned off, initiating a process that ultimately activates cancer genes. SOX9’s ability to pry open sealed pockets of genetic material and bind to previously silent genes within can kickstart malignant growth.
What are “pioneer factors,” and how do they relate to SOX9?
Pioneer factors are a unique class of proteins that can unlock genetic packets within closed chromatin, recognizing binding sites within and activating new genes. SOX9 is identified as a pioneer factor, allowing it to access closed chromatin and activate dormant genes, which in turn can lead to cancer development when misregulated.
What new insights or potential treatments does the research on SOX9 provide?
The research on SOX9 provides insights into how cancer derails a stem cell’s carefully tuned decision-making process and how SOX9’s misregulation can lead to cancer. By understanding how SOX9 operates as a pioneer factor and its role in malignancy, researchers hope to find new drug targets for some of the most deadly cancers, highlighting SOX9-activated genes as potential therapeutic targets.
How did the researchers study SOX9’s role in cancer?
The researchers engineered mice that contained a copy of SOX9 that could be activated in their adult epidermal stem cells. They then tracked the epigenetic process, discovering how SOX9 turned off epidermal stem cell genes and activated hair follicle stem cell genes. By exploring this process, they were able to understand how SOX9 hijacked nuclear machinery and activated previously silent genes, leading to cancerous states.
5 comments
Wow this is really something else! Never knew SOX9 was such a big deal in cancer research. Can this mean a breakthrough for a cure?
This is complicated stuff, but it seems important. Can anyone explain this in simpler terms? whats a pioneer factor, exactly?
I lost my dad to lung cancer, reading about research like this gives me hope. i really believe we’ll find a cure someday. Thank you scientists for all your hard work.
honestly didnt think that transcription factors like SOX9 can have such dark sides! its like a double-edged sword. hope the researchers find a way to stop it.
thats fascinating, but also scary. the way SOX9 can just switch cells fates, makes you wonder what else is hiding in our DNA. Keep up the great work Rockefeller researchers!