More on Myc: meet the “Miz’s” in our new paper

I recently did a post telling you about one of my favorite molecules, Myc, which is important not only in cancer but also in most, if not all stem cells including iPS cells.

There’s a lot more to Myc and how it does it’s tricks in embryonic stem cells and iPS cells. It cannot do it alone and needs a partner called Miz-1.

My lab just published a new paper on Myc’s function in human ES cells, which included some genomics studies showing just how much Myc and Miz-1 work together like a Mr. and Mrs.

One of the take home messages from the paper is that a key role for Myc in maintaining (human ES cells) and inducing (iPS cells) pluripotency appears to be turning off expression of genes that promote differentiation.

You can think of Myc as the anti-differentiation agent.

This anti-differentiation function for Myc may have a lot to do with why too much Myc causes cancer; excess Myc locks in an undifferentiated state in stem cells changing them into cancer stem cells. In non-stem cells, too much Myc may actually de-differentiate them into cancer stem cells.

But Myc cannot do this anti-differentiation stuff alone. In fact, Myc has a known partner called Max, but it turns out that most likely Max is not the main helper for Myc when it comes to directly blocking differentiation in stem cells. Instead it is a protein called Miz-1.

Miz-1 is a zinc-finger protein that we found works together with Myc to keep differentiation genes in stem cells in the “OFF” position. One interesting thing is that Miz-1 alone turns genes on and Myc alone turns genes on, but when they work together they do the opposite–they turn genes off and it is specifically differentiation genes that they target as a dynamic duo.

One of the big surprises of our paper was that in human ES cells that the location of Myc and Miz-1 action in the genome was not where most of us thought it would be based on previous studies in cancer cells.  While it was predicted that they would work right at the beginning of genes as they do in cancer cells, surprisingly in human ES cells Myc and Miz-1 most often work to regulate genes by acting further away.

Why the apparent difference between how they work in ES cells and cancer cells? That remains an important open question we hope to figure out in the future. Many other important open questions remain as well.