All tags epigenetics Scientist of the month: Mitzi Kuroda

Scientist of the month: Mitzi Kuroda

Mitzi Kuroda talks to us about her research into chromatin organization in Drosophila and human cancer cells.

Brief biography

Mitzi Kuroda, PhD

Mitzi Kuroda is a Professor of Genetics and of Medicine at Harvard Medical School and Brigham and Women’s Hospital. She studies chromatin organization and epigenetic regulation in Drosophila and in human cancer cells. 

Mitzi is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. She received her BS degree in Biology from Tulane University and her PhD in Biological Sciences from Stanford University, where she worked with Charles Yanofsky. 

After postdoctoral studies at Stanford, she became a faculty member at Baylor College of Medicine before moving to Harvard Medical School in 2003. Mitzi has been an NSF Presidential Young Investigator, Searle Scholar, Howard Hughes Investigator, and has served on the Board of Directors of the Genetics Society of America, the North American Dros​ophila Board and ad hoc on the NIH National Advisory General Medical Sciences Council.

What made you decide to become a scientist?

When I learned about recombinant DNA in college, it captured my imagination. I had to toss aside all my plans to “save the world” because the ability to make specific DNA molecules for molecular genetic experiments was just too enticing.

What exciting research projects are occurring in your lab?

Although my lab has focused on gene expression in Drosophila for most of my career, we have recently applied our expertise in chromatin biology to cancer research. In particular, we have teamed up with Dr. Chris French, a pathologist, in the study of NUT-midline carcinoma (NMC).

BRD4-NUT, a translocation-encoded fusion protein, plays a defining role in NMC. Together, our labs have discovered that nuclear foci containing BRD4-NUT protein correspond to extremely broad, cell type-specific, hyperacetylated chromatin domains in patient tissue and cell lines. These are much larger than typical activated regions or super-enhancers, ranging from 100 kb to 2 mb.

These megadomains appear to reflect a pathologic, feed-forward regulatory loop in which hyperacetylation drives further bromodomain-dependent binding and aberrant transcriptional activity. The novelty of megadomains is that they spread from select pre-existing enhancers (surprisingly not enriched for recently described super-enhancers) to fill individual topologically associating domains (TADs). Although the selected TADs generally differ by cell type, the c-MYC and TP63 regions are targeted in all NMC patient cells examined to date.

The ability to spread to fill whole regulatory compartments surrounding genes encoding proteins like MYC and p63 is likely to explain the extremely aggressive nature of NUT midline carcinoma. We are currently identifying BRD4-NUT protein partners that might be amenable to therapeutic inhibition of NMC, to work in conjunction with existing bromodomain inhibitors for BRD4.

How did you first become interested in dosage compensation?

I worked on transcription attenuation in bacteria as a graduate student with Charley Yanofsky and I hoped to continue studying unusual forms of regulation in my future work. The mysterious dosage compensation of the male X chromosome in flies seemed like it had to have some unusual solution. This turned out to be the case, with histone modifications, X chromosome-specific proteins, and noncoding RNAs all playing important roles.

You recently extended your studies to the Polycomb repressive complexes. What made you focus on this topic?

Our genomic studies of dosage compensation led us to realize that we needed new approaches to identify protein interactions that might be destabilized by the conditions required for removal from chromatin. 

We developed BioTAP-XL, in which the crosslinked DNA, RNA, and protein fractions for specific chromatin complexes are affinity purified together and then analyzed in parallel by comprehensive sequencing and mass spectrometry. When we realized how well this worked, we decided to broaden our scope to study the Polycomb group proteins, given their beautiful genetics in flies and their central role in human diseases such as cancer.

Where do you see the field of Epigenetics going in the next 5–10 years?

I hope we can convince more labs to try BioTAP-XL analyses to decipher their protein complexes and sub-complexes! But seriously, understanding the dynamic protein modifications that must govern combinatorial control of just about any genetic pathway is a huge challenge that I hope will be surmounted. 

Also, it will be fascinating when epigeneticists can identify all of the genomic annotation (including chromatin marks, and maybe even bound RNAs and proteins) that may persist through the germline to specify the next generation. 

Do you have any advice to those starting their careers in research?

The beauty and difficulty in biology is that the questions to be asked are still really wide open. Whatever you decide to work on, you should constantly assess whether you are really getting to the most interesting questions in that system.  Try not to do the same thing as everyone else, but if the questions to be asked are clearly the right ones don’t be overly afraid of competition either. Multiple perspectives can really move things forward.

What would you be working on if you weren't a scientist?        

I would have tried to study the world and how to make it a better place, politically. And undoubtedly been very frustrated.

One thing that you could not live without? (inside or outside the lab)    

Besides the obvious (family and food/water/air), I think the answer would be my daily dose of new information. I start with the New York Times every morning, and proceed from there. The steady-state amount that I know at any one time probably doesn’t increase so much these days, but I enjoy replacing the old with something new.



References  

Alekseyenko AA, Walsh EM, Wang X, Grayson AR, Hsi PT, Kharchenko PV, Kuroda MI, French CA (2015). The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains. Genes Dev 29, 1507–1523

Kang HJ, McElroy KA, Jung YL, Alekseyenko AA, Zee BM, Park PJ, Kuroda MI (2015). Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes in Drosophila. Genes Dev 29, 1136–1150.

Ho JWK, Jung YL, Liu T + ModEncode Consortium (2014). Comparative analysis of metazoan chromatin organization. Nature 512, 449–452.

Alekseyenko AA, Gorchakov AA, Zee BM, Fuchs SM, Kharchenko PV, Kuroda MI (2014). Heterochromatin-associated interactions of Drosophila HP1a with dADD1, HIPP1, and repetitive RNAs. Genes Dev 28, 1445–1460.

Ferrari F, Plachetka A, Alekseyenko AA, Jung YL, Ozsolak F, Kharchenko PV, Park PJ, and Kuroda MI (2013). “Jumpstart and gain” model for dosage compensation in Drosophila based on direct sequencing of nascent transcripts. Cell Rep 5, 629–636.

Larschan E, Bishop EP, Kharchenko PV, Core LJ, Lis JT, Park PJ, Kuroda MI (2011). X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. Nature 471, 115–118.
Sign up