Every stem cell faces a decision to become a mature epidermal cell or switch to becoming a hair follicle cell. This so-called fate switch is governed by the transcription factor SOX9. If the progenitor cell expresses SOX9, hair follicle cells develop. If it doesn’t, epidermal cells do. However, SOX9 is implicated in many of the deadliest cancers worldwide, including lung, skin, head and neck, and bone cancers.

Scientists have never fully understood how this outcome occurs at a molecular level. Now Rockefeller researchers have revealed the mechanisms behind this malignant turn of events. Their findings are published in Nature Cell Biology in an article titled, “The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.”

“During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers,” the researchers wrote. “Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching.”

The researchers discovered SOX9 belongs to a special class of proteins that govern the transfer of genetic information from DNA to mRNA. It has the ability to pry open sealed pockets of genetic material, bind to previously silent genes within, and activate them.

“Our discovery provides new insights into how cancer derails a stem cell’s carefully tuned decision-making process, thereafter making it impossible for it to make normal tissue,” said Elaine Fuchs, PhD, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. “It also illuminates new SOX9-activated genes as potential therapeutic targets.”

“In the disease context, SOX9 gets reactivated in adult epidermal stem cells,” said Yihao Yang, a graduate student at Rockefeller and first author of the study.

How this process might unfold step by step has been unknown, Yang added. “Reprogramming in vitro happens really fast—within 48 hours. With such a short time window, it’s hard to get a good resolution on the sequence of events.”

The researchers engineered mice that contained a copy of SOX9 that could be activated in their adult epidermal stem cells when the mice were fed doxycycline, a drug that induced the transgenic SOX9.

“In adult tissues, choices that were easily made in embryogenesis are tightly suppressed so that adult stem cells stick to their dedicated task,” explained Fuchs.

“By only expressing this single SOX9 transcription factor,” Yang said, “we were able to induce basal cell carcinoma-like structures by week six. By week 12, we started to see lesions that resembled human basal cell carcinoma.”

Simultaneously, they tracked the epigenetic process going on behind the scenes. In the first two weeks, SOX9 turned off the epidermal stem cell genes. Reversing their normal state, they began to turn on hair follicle stem cell genes.

Seeking the mechanism, the researchers discovered that to achieve this fate switch, SOX9 hijacked the nuclear machinery from the active epidermal genes and brought this stolen equipment to the silent hair follicle genes. It then enlisted other transcription factors to pry open the closed chromatin bind to the silent genes within, turning them on.

“When SOX9 could not be regulated, the stem cells failed to make hair but instead just kept proliferating and activating several new transcription factors, eventually leading to a basal cell carcinoma state,” Fuchs said.

This complicated, identity-shifting back-and-forth was only possible because SOX9 is a pioneer factor, Yang said. “Only a pioneer factor has the ability to access closed chromatin,” he pointed out.

Because SOX9 is overly active in many of the deadliest cancers worldwide, the researchers aim to look for ways to intervene in its role in proliferating these cells. “By identifying how SOX9’s interacting proteins and its target genes change during malignancy, we hope to make inroads into unearthing new drug targets for these cancers,” Fuchs said.

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