Two Proteins Safeguard Skin Stem Cell Function

Ever scraped your knees or elbows? It’s a good thing that they didn’t stay that way, since human skin readily renews, heals wounds, and regenerates the hair that covers it thanks to a resident population of stem cells. These cells continually produce new ones. Depending on someone’s age, the complete skin is renewed every 10-30 days.

A new study led by Salvador Aznar Benitah (Institute for Research in Biomedicine, Barcelona, Spain) has identified two proteins that are integral to the conservation of skin stem cells. Without these proteins these skin-based skin cells are lost.

The proteins identified, Dnmt3a and Dnmt3b, trigger the first step of the genetic program that leads to stem cell renewal and regeneration of the skin. “Without them (i.e. Dnmt3a & Dnmt3b), this program is not activated and the stem cells collapse and disappear from the tissue,” said Benitah.

Dnmt3a & 3b are enzymes that attach methyl groups (-CH3) to the cytosines in DNA molecules.  The full name of these enzymes, DNA (cytosine-5)-methyltransferase 3A, catalyze the transfer of methyl groups to specific CpG structures in DNA.  This process is known as “DNA methylation.”  These particular DNA methyltransferases participate in de novo DNA methylation.  They must be distinguished from so-called “maintenance DNA methylation,” which ensures the fidelity of replication of inherited epigenetic patterns.

Epigenetics refers to cellular and physiological trait variations that result from external or environmental factors that switch genes on and off and affect how cells express genes, but do not involve changes in nucleotide sequences, but in chemical modifications to DNA or higher-order structures of DNA.

DNMT3A forms part of the family of DNA methyltransferase enzymes that includes DNMT1, DNMT3A and DNMT3B.  While de novo DNA methylation modifies the information passed on by parents to their progeny, it enables key epigenetic modifications essential for processes such as cellular differentiation and embryonic development, transcriptional regulation, heterochromatin formation, X-inactivation, imprinting and genome stability.

Lorenzo Rinaldi, a graduate student in Benitah’s laboratory who was also the first author of this study, has mapped the regions of the genome that houses the genes that encodes these two proteins. Rinaldi and others have shown that Dnmt3a & 3b affect gene expression by methylating “gene enhancers” and “superenhancers.” Gene enhancers and superenhancers are sequences that tend to be far away from genes but still have the ability to increase the speed of gene expression up to 200-fold.

“It was surprising to see that two proteins that have always been associated with gene repression through DNA methylation are activated in the most transcriptionally active regions of stem cells. We had never observed this activity because we were unable to study the global distribution of Dnmt3a and Dnmt3b at the genomic level. Thanks to advances in sequencing techniques, more researchers are observing the very mechanism that we have described,” said Rinaldi.

Of the 12,000 gene enhancers in the genome, about 300 are superenhancers related to stem cell activity. Dnmt3a & 3b activate expression of the approximately 1,000 genes that are required for the self-renewing capacity of stem cells. By methylating the superenhancer, these proteins trigger the first step of the machinery that leads to the amplified expression of these essential genes for the stem cell.  Dnmt3a and Dnmt3b clearly associate with the most active enhancers in human epidermal SCs.


The expression of Dnmt3a & 3b is also altered in cancer cells. Cancer cells tend to show altered DNA methylation and altered gene enhancers that affect gene expression. The mass sequencing of tumor cell genomes has provided these observations. Dnmt3a and Dnmt3b activities are altered in many types of tumor, including leukemias, and cancers of the lung and the colon.

“Each of these three components is associated with the development of various kinds of cancer. Given that these proteins activate gene expression enhancers through DNA methylation, we believe that it would be of interest to study them in cancer cells in order to determine whether they participate in tumor development,” said Benitah.

This work appeared in: Lorenzo Rinaldi et al., “Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis,” Cell Stem Cell, July 2016 DOI: 0.1016/j.stem.2016.06.020.