Yamanaka may have found a way to give exogenous Myc the boot from the iPS cell universe.
It has always been a frustration in the iPS cell field that Myc, a proto-oncogene, is so important for reprogramming. Yes, you can make iPS cells (especially mouse) without Myc, but it can be orders of magnitude harder, especially when making human iPS cells. And if you end up with just a little bit too much Myc, the cells can become cancerous.
While Myc may not be intrinsically a stem or pluripotency-specific factor, stem cells sure love their Myc. Without at least some amount of Myc, either endogenous or exogenous, ES cells and iPS cells lose their identity.
Now Yamanaka has seemingly found a strong replacement for Myc in the form of a newly identified pluripotency factor called Glis1. This paper will come out in tomorrow’s Nature, but you can read it here.
What’s the scoop on this paper?
Yamanaka’s team screened more than 1,400 human transcription factors for the ability to replace either KLF4 or OCT4/POU5F1. They found 18 factors that could replace KLF4 but intriguingly none that could replace OCT4. Thus, OCT4 seems to be the most important stem cell factor as has now been thought for several years. The list of the 18 factors that can replace KLF4 is here on page 15 of the supplemental data. One of these eighteen is a factor called Glis1.
What the heck is Glis1? Glis1 is a zinc finger transcription factor member of the Gli family. Rather than having a similar function as Myc, Glis1 works at least in part apparently by inducing endogenous Myc levels as well as Nanog and Lin28, other important pluripotency factors.
Interestingly, Myc still enhances the process of iPS cell formation even when added in the presence of Glis1.
Glis1 expression is normally largely limited to the very early embryo, a profile similar if not identical to OCT4.
It is also worth noting that Glis1 specifically seems to turn on expression not of c-Myc, but rather family members L-myc and N-myc. In fact, Glis1 suppresses c-Myc expression. This further supports the notion that Myc family members are not all created equal. Intriguingly, Glis1 binds all 3 Myc genes directly, but somehow ends up repressing c-Myc while it turns on the expression of the other two Myc family members.
This is a really important paper, but some equally important questions remain.
Are Glis1 iPS cells safer? While Glis1 did not apparently increase mortality in mice derived from Glis1-produced iPS cells, it remains unclear if Glis1 might have an oncogenic function. In fact it would be surprising if it didn’t given that not just Myc, but essentially all pluripotency factors are oncogenic or highly expressed in malignant tumors.
If Glis1 turns up Myc expression, could that make cells behave in a more tumorigenic manner? It’s unclear, but it is a concern. Even transiently high levels of Myc can lead to genomic instability and oncogenic transformation.
Is Glis1 expressed at high levels or amplified in human cancers? The paper does not comment on this and a brief database search did not find any connection, but there is very little if any data on this.
What is the normal function of Glis1 in early development? Who knows, but could be to keep N-Myc (and possibly L-Myc) levels high in the very early embryo.
There are currently only 2 articles in Pubmed with Glis1 in the title, but you can bet that over the next couple years that will dramatically increase. Stay tuned!