Many of this blog’s readers ask about my own lab’s research. What is the focus of the work in the Knoepfler Lab?
You can go check out our lab website, but I thought it might be time again to blog about what we are all about as a lab and what we have been up to most recently. I am fortunate to have an exceptional team of researchers in my lab.
Our mission is to advance knowledge toward two main goals: (1) the development of new, safe, and effective stem cell-based regenerative medicine therapies, and (2) catalyzing novel cancer therapies, particularly for childhood brain tumors and other pediatric neuronal cancers. Related to this, we are also investigating how the brain normally grows during development. In short, the research we do mainly converges towards the goal of advancing science to get new stem cell and cancer therapies off the ground. To this end we use innovative molecular, developmental, and cellular biological techniques as well as genetics and genomics approaches.
We are particularly interested in a field of science called epigenetics. We all know about the genome where our genes are coded, but the genome doesn’t do anything without the epigenome (global and specific epigenetic events), which consists primarily of DNA methylation and histone modifications. Each cell’s epigenomic state orchestrates the genes that are on and off, which in turn collectively controls how that cell behaves (e.g. how a stem cell stays a stem cell or differentiates) or in the case of cancer and other diseases, how it misbehaves. We recently published a review article on the connections between epigenetics, cancer, and stem cells.
As it turns out, stem cells and cancer cells are unfortunately highly related cell types, perhaps even cellular siblings. For example, we showed in a novel paper a couple years back that the process of cellular reprogramming to make iPS cells is in some ways remarkably similar to the process of turning normal cells into cancer cells. This paper has stirred quite a bit of discussion.
What else have we been up to lately?
Supported by NIH and Alex’s Lemonade Stand Foundation, we are working on three main areas and you can see these themes reflected in the list of our recent publications.
First, we have a long-standing interest in a cancer-related gene called MYC. Some have speculated that every human cancer in one way or another has some problem with MYC, usually too much of it. At the same time, however, Myc proteins are essential for normal stem cell function. As a result Myc ends up being quite the Dr. Jekyll and Mr. Hyde kind of character. As with any molecule or person for that matter, Myc does not act alone. Lately we’ve been getting more interested in a key cofactor of Myc called Miz-1.
Second, we are excited about a relatively newer area of epigenetic and chromatin research focused on a molecule called histone variant H3.3. Histones come in different forms and histone variants are cool and interesting because they don’t follow the normal rules for histones. Histone variants such as H3.3 can become part of chromatin (the combination of DNA and histones) basically any time in any kind of cells. For most histones their ability to do that is much more sharply constrained. This makes a variant such as H3.3 far more dynamic and important to decision-making processes by cells such as stem cells and cancer cells.
In the case of H3.3, two genes make the same identical H3.3 protein. We call these genes A and B, short, for H3f3a and H3f3b. In 2013 we reported in our Bush, et al. paper the phenotype of the first knockout of an H3.3-coding gene in mice with our knockout of the B gene. About half the time, mice lacking the B gene do not make it through development and have a host of problems including an inability to properly segregate their chromosomes during cell division that leads in turn to DNA damage and apoptosis (cell death). The surviving B knockout mice are pretty much all infertile. It’s notable that mutations in H3.3 occur in humans and are strongly linked to childhood cancer. Last year we also published a review article in Cancer Cell on the H3.3-cancer connection, which involves two particularly disastrous tumors in children called glioblastoma and DIPG. We are excited about our new H3.3 paper on its function in germ cells, which I discuss in more depth here including its relevance for brain tumors. In the image above you can see H3.3 loss-of-function testes with unusual histone mark levels.
Third, we are studying two genes that also function in stem cells and cancer called DPPA4 and DPPA2. It is fascinating to think about how certain genes like these, H3.3, and Myc, can function normally in stem cells, but then with a monkey wrench in the system they can cause cancer. In the case of DPPA4 and DPPA2, they have long been known to be important stem cell genes, but it was only in 2013 that our lab discovered and published in the journal Stem Cells that they are also oncogenes. Surprisingly, it is still largely an open question how the Dppa4 and Dppa2 proteins actually work.
Overall one can see that we work at the interface of stem cells, cancer, and developmental tissue growth and investigate how epigenetic machinery orchestrates the regulatory events involved.
Finally, we are committed to educational outreach and advocacy for evidence-based innovative medical treatments and regenerative medicine therapies.