March 29, 2016

Meet Adriana Gonzalez

Adriana Gonzalez has recently completed her PhD thesis in Susan Gasser’s laboratory. During her thesis she identified a much sought-for anchor protein—the previously uncharacterized CEC-4—that directly sequesters inactive chromatin at the nuclear membrane and identified a new paradigm for the contribution of nuclear anchoring towards stabilizing cell fate decisions.

Q: You analyzed in C. elegans how DNA is anchored to the nuclear periphery to stabilize an induced cell fate. Why is chromatin organization inside the nucleus important at all?
Adriana Gonzalez: In general, the hypothesis is that the different compartments make chromatin-related processes more efficient: Factors that are needed for repression or activation would accumulate in a certain nuclear compartment, reinforcing a silenced or active state, respectively.
Even though this is still highly speculative, there are lots of studies correlating gene repression with proximity to the nuclear periphery. But there was no direct proof yet. Moreover, heterochromatin is enriched to the nuclear periphery during differentiation, so many people thought that it might be involved in differentiation per se.
Our study in C. elegans embryos has three main messages. (1) The mechanism for anchoring of heterochromatin described by Benjamin Towbin, a former PhD student in the lab, in 2012, relies on the previously uncharacterized CEC-4 protein, which recognizes H3K9 methylation on chromatin, to position it to the nuclear periphery. (2) Anchoring of chromatin is not directly involved in the expression status of genes. Or in other words, when CEC-4 was deleted and chromatin is away from the periphery, we saw no differences in gene expression. This was unexpected, and was never shown before in a living organism. (3) Only under forced induction of a muscle differentiation program, anchoring was shown to be important for the commitment to this cell fate.
Importantly, cec-4 mutant embryos develop to form worms, excluding the possibility that at these early stages of development anchoring is crucial for proper development. However, our forced cell fate induction shows that anchoring can help to stabilize an abrupt change in the differentiation program.

Q: What has fascinated you, when you decided to study this phenomenon?
A: At first, I was fascinated by the simplicity of the question. A really basic observation that people are still struggling to understand. Of course when you get into the field, you understand why people don’t have a clear answer yet! Many cells in our body with totally different functions localize heterochromatin to the nuclear periphery. And the phenomenon is also highly conserved between species. “What is it good for?” was always the driving question behind our work.

Q: Your results were recently published in Cell, your project has come to an extremely successful end. However, I can imagine that—as often in science—not everything ran that smoothly. What was the biggest challenge in this project? And what helped you in these instances?
A: The beginning of my PhD, when I started characterizing the molecular mechanism of anchoring by CEC-4, went smoothly. The biggest challenge came when we had to find the functionality of anchoring, knowing that there were no differences in gene expression regardless of whether chromatin was anchored or not under normal conditions. Discussions and suggestions from Susan, my group leader, Benjamin and people in and out of the laboratory were fundamental at this stage.

Q: What was the biggest positive surprise?
A: One of the biggest surprises was to find that CEC-4 localizes at the nuclear periphery. It was a big moment, when we actually saw rings of the protein at the nuclear periphery. With this, CEC-4 was perfectly suited for chromatin anchoring. In the past, people in the field identified other anchoring-related factors, but these factors were not necessarily enriched at the nuclear periphery, making it difficult to address their mechanism of action. In the case of CEC-4, the hypothesis to follow was simple: “CEC-4 sits at the nuclear periphery to anchor chromatin directly”.

Q: Many scientists have a strong intrinsic motivation to dig into the questions that interest them. What has instilled your interest in biological sciences?
A: My interest has always been to understand cell differentiation and development. Many laboratories focus on understanding cell differentiation through transcription factors and regulatory networks. Positioning of chromatin at the nuclear periphery has been somehow implicated in this process, and to me it was exciting to possibly link this chromatin organization phenomenon with differentiation and development.

Q: You are from Mexico and have decided to pursue your PhD in Switzerland. What attracted you to the FMI and to Switzerland?
A: A good friend of mine from my Bachelor in Mexico, who already started her PhD in Switzerland, recommended to me the NCCR program, and luckily I was selected for it. The type of science done in Switzerland is of such high quality, I felt it was a perfect place to interact with good scientists and learn from them.
In this NCCR program, we had a first year of rotations. I did one at CMU Geneva, one at the EPFL Lausanne and one with Susan at the FMI. I was able to compare all these good institutes and different labs and my conclusion was that the FMI offered a great scientific environment. The good communication among labs and the FMI facilities stood out. Sharing ideas, reagents and fun always happens at the FMI. Our work is what it is, thanks to the experienced people the FMI has in its facilities.

» More about Adriana’s work
» More about the interests of Susan Gasser’s laboratory

Original publication
Gonzalez-Sandoval A, Towbin BD, Kalck V, Cabianca DS, Gaidatzis D, Hauer MH, Geng L, Wang L, Yang T, Wang X, Zhao K, Gasser SM (2015) Perinuclear anchoring of H3K9-methylated chromatin stabilizes induced cell fate in C. elegans embryos. Cell doi: 10.1016/j.cell.2015.10.066. [Epub ahead of print]

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