Media Releases

University of Toronto cell biologists discover on-off switch for key stem cell gene

December 16, 2014

Discovery may propel advances in regenerative medicine

TORONTO, ON – Con­sid­er the rela­tion­ship between an air traf­fic con­troller and a pilot. The pilot gets the pas­sen­gers to their des­ti­na­tion, but the air traf­fic con­troller decides when the plane can take off and when it must wait. The same rela­tion­ship plays out at the cel­lu­lar lev­el in ani­mals, includ­ing humans. A region of an animal’s genome – the con­troller – directs when a par­tic­u­lar gene – the pilot – can per­form its pre­scribed func­tion.

A new study by cell and sys­tems biol­o­gists at the Uni­ver­si­ty of Toron­to (U of T) inves­ti­gat­ing stem cells in mice shows, for the first time, an instance of such a rela­tion­ship between the Sox2 gene which is crit­i­cal for ear­ly devel­op­ment, and a region else­where on the genome that effec­tive­ly reg­u­lates its activ­i­ty. The dis­cov­ery could mean a sig­nif­i­cant advance in the emerg­ing field of human regen­er­a­tive med­i­cine, as the Sox2 gene is essen­tial for main­tain­ing embry­on­ic stem cells that can devel­op into any cell type of a mature ani­mal.

“We stud­ied how the Sox2 gene is turned on in mice, and found the region of the genome that is need­ed to turn the gene on in embry­on­ic stem cells,” said Pro­fes­sor Jen­nifer Mitchell of U of T’s Depart­ment of Cell and Sys­tems Biol­o­gy, lead inves­ti­ga­tor of a study pub­lished in the Decem­ber 15 issue of Genes & Devel­op­ment.

“Like the gene itself, this region of the genome enables these stem cells to main­tain their abil­i­ty to become any type of cell, a prop­er­ty known as pluripo­ten­cy. We named the region of the genome that we dis­cov­ered the Sox2 con­trol region, or SCR,” said Mitchell.

Since the sequenc­ing of the human genome was com­plet­ed in 2003, researchers have been try­ing to fig­ure out which parts of the genome made some peo­ple more like­ly to devel­op cer­tain dis­eases. They have found that the answers are more often in the regions of the human genome that turn genes on and off.

“If we want to under­stand how genes are turned on and off, we need to know where the sequences that per­form this func­tion are locat­ed in the genome,” said Mitchell. “The parts of the human genome linked to com­plex dis­eases such as heart dis­ease, can­cer and neu­ro­log­i­cal dis­or­ders can often be far away from the genes they reg­u­late, so it can be dif­fi­cult to fig­ure out which gene is being affect­ed and ulti­mate­ly caus­ing the dis­ease.”

It was pre­vi­ous­ly thought that regions much clos­er to the Sox2 gene were the ones that turned it on in embry­on­ic stem cells. Mitchell and her col­leagues elim­i­nat­ed this pos­si­bil­i­ty when they delet­ed these near­by regions in the genome of mice and found there was no impact on the gene’s abil­i­ty to be turned on in embry­on­ic stem cells.

“We then focused on the region we’ve since named the SCR as my work had shown that it can con­tact the Sox2 gene from its loca­tion 100,000 base pairs away,” said study lead author Har­ry Zhou, a for­mer grad­u­ate stu­dent in Mitchell’s lab, now a stu­dent at U of T’s Temer­ty Temer­ty Fac­ul­ty of Med­i­cine. “To con­tact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embry­on­ic stem cells. Once we had a good idea that this region could be act­ing on the Sox2 gene, we removed the region from the genome and mon­i­tored the effect on Sox2.”

The researchers dis­cov­ered that this region is required to both turn Sox2 on, and for the embry­on­ic stem cells to main­tain their char­ac­ter­is­tic appear­ance and abil­i­ty to dif­fer­en­ti­ate into all the cell types of the adult organ­ism.

“Just as dele­tion of the Sox2 gene caus­es the very ear­ly embryo to die, it is like­ly that an abnor­mal­i­ty in the reg­u­la­to­ry region would also cause ear­ly embry­on­ic death before any of the organs have even formed,” said Mitchell. “It is pos­si­ble that the for­ma­tion of the loop need­ed to make con­tact with the Sox2 gene is an impor­tant final step in the process by which researchers prac­tic­ing regen­er­a­tive med­i­cine can gen­er­ate pluripo­tent cells from adult cells.”

“Though the degree to which human embry­on­ic stem cells pos­sess this fea­ture is not entire­ly clear, by under­stand­ing how anoth­er com­plex organism’s genome works we ulti­mate­ly learn more about how our own genome works,” said Zhou.

The find­ings are report­ed in the arti­cle “A Sox2 dis­tal enhancer clus­ter reg­u­lates embry­on­ic stem cell dif­fer­en­ti­a­tion poten­tial” pub­lished online Decem­ber 15 in Genes & Devel­op­ment.

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For more infor­ma­tion, please con­tact:

Jen­nifer Mitchell
Depart­ment of Cell and Sys­tems Biol­o­gy
Uni­ver­si­ty of Toron­to
416–978-6711 (B)
416–500-6833 ©
ja.mitchell@utoronto.ca

Har­ry Zhou
Temer­ty Temer­ty Fac­ul­ty of Med­i­cine
Uni­ver­si­ty of Toron­to
647–823-8323 ©
harry.zhou@mail.utoronto.ca

Sean Bet­tam
Com­mu­ni­ca­tions, Fac­ul­ty of Arts & Sci­ence
Uni­ver­si­ty of Toron­to
416–946-7950
s.bettam@utoronto.ca

Jes­si­ca Lewis
Com­mu­ni­ca­tions, Fac­ul­ty of Arts & Sci­ence
Uni­ver­si­ty of Toron­to
416–978-8887
jessica.lewis@utoronto.ca