MS, Biology, National Institute of Agriculture Technology, Biotechnology Institute and University of Buenos Aires
PhD, Biology, National Institute of Agriculture Technology, Biotechnology Institute and University of Buenos Aires
As a doctoral student at the Institute of Agriculture Technology and the University of Buenos Aires studying molecular biology, Ariel Bazzini, PhD, was fascinated by RNA, and especially messenger RNA (mRNA), a molecule well-known for translating the DNA code into the amino acids that make up proteins. “I became very excited with the idea that while each cell in our body has largely the same DNA information, what makes them so different is their mRNA,” Bazzini says.
Bazzini first studied RNA in depth while investigating how viruses affect gene expression in plants during his doctoral dissertation work at the Institute of Biotechnology in Argentina’s National Institute of Agricultural Technology and the University of Buenos Aires. Wanting to continue his genetics studies in animals, Bazzini took a postdoctoral fellowship position with Yale University’s Antonio Giraldez, PhD, who was researching microRNA in zebrafish. During this position, Bazzini successfully adapted the ribosome profiling technique (for the first time in a whole embryo) to measure translation in vivo in order to understand the large range of translation levels between mRNAs in a cell. Bazzini initially used this state-of-the-art technique to demonstrate that miRNAs prevent first translation and then RNA decay during embryogenesis.
Then, Bazzini used ribosome profiling to define the coding region of the entire zebrafish transcriptome. For example, he identified small translated coding regions in 5’ and 3’ “untranslated regions” (UTRs), as well as in genes that were annotated as non-coding. Later, he showed that coding regions in the 5’UTR are translational repressors.
Finally, Bazzini was also interested in understanding what defines the stability of the mRNAs. The leading hypothesis was that regulatory sequences found within the 3’ UTRs of mRNAs account for their post-transcriptional regulation (e.g. microRNA). However, the large majority of mRNAs were degraded by unknown mechanisms. He discovered that codons, the three-nucleotide ‘words’ read by the ribosome, have a strong effect on the stability of maternal mRNA and thus contain cis-regulatory information that extends far beyond the amino acids they encode. This represents a paradigm shift in how mRNA stability is viewed.
Next to his research, Bazzini’s other passion is sharing his scientific knowledge and supporting up-and-coming scientists from his home country of Argentina, as well as neighboring countries in South America. He heads south every year to give scientific lectures. “There are amazing students and scientists from South America,” he says.
When he’s not in the lab, Bazzini enjoys spending time with his wife, daughter, and son. He also plays soccer, a passion of his since he was a child growing up in Buenos Aires. “I started kicking the ball as soon as I learned how to walk,” he says. “Like most kids in Argentina, I dreamed of playing for the national team.”
The Bazzini Lab is interested in how genes are regulated to impact development, physiology, and disease. Bazzini and his colleagues are exploring how mRNA stability and mRNA translation are regulated. Traditionally, transcription has been thought to be the major determinant of mRNA level. “The canonical view has been that RNA equals transcription. However, the stability of the mRNA can also strongly affect the level of RNA, therefore RNA equals transcription plus stability,” he says. “And we seek to understand what dictates the stability of the mRNA in vertebrates.”
The assumption that mRNAs in higher organisms translate a single coding region (ORF) has undergone a dramatic revision in recent years. Bazzini has identified thousands of small translated ORFs within previously assigned UTRs and long non-coding RNAs. Upon analyzing ribosome profiling data from human cell lines and zebrafish embryos, the Bazzini team has discovered translated small ORFs in the 3’UTR, which they refer to as downstream open reading frames (dORFs). Unexpectedly, they found that these dORFs strongly enhance translation of the main coding ORF.
In aquatic vertebrate organisms such as zebrafish (Danio rerio), attempts to establish efficient knock-down mRNA have largely failed. The Bazzini group has shown that CRISPR-Cas13d is an effective and precise system to deplete specific mRNA transcripts in zebrafish embryos. Moreover, they showed that this system can be used in medaka, killifish, and mouse embryos. Therefore, the CRISPR-Cas13d system is the first systematic platform to efficiently knockdown mRNA levels to interrogate gene function in animal embryos.
Bazzini looks forward to where the collaborative nature of the Stowers Institute takes him and his research. “I have been very fortunate with the group of people I’ve assembled in my lab. They are absolutely fearless to jump into any type of experiment,” he says, adding that the Stowers Institute gives them the freedom to take risks. “We don’t just do science that we can do or that we feel comfortable doing. It’s about doing the science that we want to do, addressing the biological questions that do not allow us to sleep or the ones that might challenge what textbooks say!”