PROFILE PROFILE Profile of Alberto Kornblihtt

Jennifer Viegas “ Science Writer adds. His wife, Professor Mirtha Flawiá, was also very important in the development of my early career. She was very enthusi- Molecular biologist Alberto Kornblihtt is Kornblihtt also enjoyed painting, drawing, astic in supporting young scientists in the ” proud to work within a tightly knit group and playing with anything mechanical. He lab to explore new research avenues. “ of Buenos Aires-based researchers who are says, IalwaysknewthatIwasgoingtobe One Gene, Many Proteins ” studying ribonucleic acids. Kornblihtt and his a scientist, but I had no idea in what field. From 1981 to 1984, Kornblihtt was a post- ’ team investigate the regulation of alternative Kornblihtt s choice of scientific field gained doctoral researcher at the Sir William RNA splicing, a process that affects nearly clarity in 1970, when he was a student at the Dunn School of Pathology in Oxford. With 90% of human genes. Kornblihtt, who was Colegio Nacional de Buenos Aires, a public Professor Francisco “Tito” Baralle, Kornblihtt elected as a foreign associate of the National high school run by the University of Buenos cloned the human fibronectin gene and Academy of Sciences in 2011, was one of the Aires. During that year, 16-year-old Kornblihtt found that the gene was alternatively first scientists to document how a single tran- took a botany and biology class given by spliced (1). The research demonstrated that scribed gene can give rise to different mes- plant taxonomist Rosa Guaglianone. “She asinglegenecouldgenerateatleast10 senger that allow the gene to express was exceptional,” he says. “We did labora- polypeptides, which are chains of amino different proteins. Because mutations that af- tory and microscope work and learned acid molecules that make up proteins. fect are a source of human about DNA, mRNA, proteins, and the ge- Until this and subsequent studies, alter- disease, the findings of Kornblihtt and his netic code. It was an exciting experience native splicing was poorly understood. It is colleagues reveal mechanisms underlying he- that marked me for the rest of my life.” now known to be a major contributor to reditary diseases, premature aging, and cancer. Kornblihtt continued his studies at the protein diversity. Kornblihtt explains, “Al- Family of Teachers University of Buenos Aires, where he majored ternative splicing is a variation of splicing in Kornblihtt was born in 1954 in the city in biology and graduated in 1977. During which each precursor messenger RNA (pre- he still calls home, Buenos Aires. “My father his doctoral thesis work in biochemistry at mRNA) molecule can give rise to different was a civil engineer who loved and taught the Campomar Foundation, his primary mature mRNAs, depending on which seg- mathematics,” he says. “My mother was a mentor was Héctor Torres. “He was a ments are joined and which are excised.” The high school teacher in geography. My oldest disciple of Luis Leloir,” Kornblihtt says, ribosome then “reads” the coding instruc- sister was a computer scientist, and my other referring to the Argentine physician and bio- tions of the mRNAs and synthesizes different sister was a kindergarten teacher, so the love chemist Leloir, who received a Nobel Prize proteins. for knowledge and education was constantly for discovering sugar nucleotides. “Torres’ Coupled Splicing and present in my childhood.” As a child, passion for discovery was contagious,” he Kornblihtt moved back to Argentina in 1984. He became a professor of molecular and cell biology at the Facultad de Ciencias Exactas y Naturales at the University of Buenos Aires, whereheremains.Soonthereafter, he began to assemble a team of researchers to study the regulation of alternative pre-mRNA splicing. A seminal achievement happened just over a decade later when, in 1997, Kornblihtt and his colleagues proved that promoters—DNA sequences that define where transcription of a gene begins—affect alternative splicing (2). Transcription is the process by which the information in a strand of DNA is copied into a new molecule of mRNA. Kornblihtt says, “This was the first evidence that tran- scription and splicing are not independent events, but that the outcome of splicing depends on the parameters of transcription.” His team has since determined that this func- tional coupling of splicing and transcription

This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article Alberto Kornblihtt. Image courtesy of Oliver Kornblihtt. on page 15622 in issue 44 of volume 111.

www.pnas.org/cgi/doi/10.1073/pnas.1421075111 PNAS Early Edition | 1of2 Downloaded by guest on September 25, 2021 reported a strategy to modify known to play a role in posttranscriptional structure at specific points in a gene by using regulation in the cell’s cytoplasm. Kornblihtt’s small noncoding RNAs (6). Inaugural Article describes how these pro- The researchers also discovered the teins also affect gene expression in the nu- mechanism by which changes in nerve cell cleus during transcription (10). In particular, activity and neuron differentiation, which can the paper provides evidence that Argonaute relax or tighten chromatin structure, pro- proteins can bind to specific locations in the mote changes in transcriptional elongation (7). genome. These locations are transcriptional Those alterations affect alternative splicing enhancers, regions in the DNA that control of genes essential for neuronal function. The team’s chromatin-related studies have con- the expression of one or multiple genes by tributed to the emerging field concerning the governing when these genes must be turned relationship between epigenetics (the study of on or off. Aberrant activation or silencing of changes in organisms caused by modification these enhancers can affect cell function and of gene expression rather than alteration of lead to cancer. “These results contribute to the DNA sequence itself) and splicing. the understanding of the complex regulation of gene expression in eukaryotic cells,” Kornblihtt UV-Induced DNA Damage and his colleagues report. In another line of investigation, Kornblihtt In addition to his position as Plenary and his team discovered the cellular mecha- Professor at the Department of Physiology, nism by which DNA damage caused by Molecular, and Cell Biology at the University UV light (UV) irradiation affects alternative of Buenos Aires, Kornblihtt is Director of the splicing (8). This mechanism is key to un- Institute of Physiology, Molecular Biology, derstanding how skin cells respond to UV The image illustrates the new emerging light contained in sunlight. Kornblihtt and and Neurosciences of the Argentine Research nuclear roles for the Argonaute 1 protein, his colleagues found that after DNA is Council, and has been an International Re- represented in the center of the picture as its damaged by UV irradiation, the cell responds search Scholar of the Howard Hughes Med- cephalopodan alter ego. Nucleosomes (in by adding new phosphate groups to the RNA ical Institute since 2002. He has won several red) are marked by specific histone mod- polymerase enzyme. This slows down the awards, including a Guggenheim Fellowship ifications (light green). Argonaute 1 binds to enzyme, thereby affecting the alternative (1991), Investigator of the Argentine Nation intragenic transcriptional enhancers through splicing “decisions” of many genes. Kornblihtt Prize, granted by the President of Argentina interactions with enhancer RNAs, and is able explains, “This promotes the death of the cells (2010), Foreign Membership in the European to affect gene regulation during transcrip- carrying the damaged DNA, preventing the Molecular Biology Organization (2012), and tion performed by RNA polymerase II (olive proliferation of mutated cells that could Diamond Award for the most relevant sci- eventually become cancer cells.” While the green) at the level of splicing of exons and entist of Argentina of the decade, ex aequo team’s studies are largely focused on human introns depicted in light cream color. Digital with physicist Juan Martín Maldacena (2013). cells in culture, they have recently extended illustration courtesy of Amagoia Agirre. Kornblihtt teaches an introductory course their work to plants. The researchers have on molecular biology at the University of shown that light and dark conditions modu- Buenos Aires. As he continues to inspire the late alternative splicing through signals that go occurs through two nonmutually exclusive next generation of Argentine scientists, from the chloroplast to the nucleus (9). mechanisms: the control of transcriptional Kornblihtt explains that he is part of a con- elongation speed (kinetic coupling) (3) and Argonaute Proteins and Gene tinuum, carrying on a long tradition of sci- the association of splicing factors to RNA Regulation entific achievers in Argentina that began with polymerase II, an enzyme that catalyzes the Argonaute proteins, which are involved in Leloir and physiologist and Nobel Laureate transcription of DNA to synthesize pre- human organ growth and development, are Bernardo Houssay. mRNA (recruitment coupling) (4). Kornblihtt says, “DNA is not naked in the nucleus.” It is instead associated with histone 1 Kornblihtt AR, Umezawa K, Vibe-Pedersen K, Baralle FE (1985) modifications affecting NCAM alternative splicing. Proc Natl proteins to form chromatin, which composes Primary structure of human fibronectin: differential splicing may Acad Sci USA 106(11):4325–4330. generate at least 10 polypeptides from a single gene. EMBO J 4(7): 6 Alló M, et al. (2009) Control of alternative splicing through siRNA- the chromosomes of organisms other than Nat Struct Mol Biol 1755–1759. mediated transcriptional gene silencing. 16(7): – bacteria. Chromatin structure, which affects 2 Cramer P, Pesce CG, Baralle FE, Kornblihtt AR (1997) 717 724. 7 Schor IE, Fiszbein A, Petrillo E, Kornblihtt AR (2013) Intragenic RNA polymerase elongation rates and alter- Functional association between promoter structure and epigenetic changes modulate NCAM alternative splicing in neuronal transcript alternative splicing. Proc Natl Acad Sci USA 94(21): native splicing, has therefore been another differentiation. EMBO J 32(16):2264–2274. 11456–11460. 8 Muñoz MJ, et al. (2009) DNA damage regulates alternative splicing focus of research for Kornblihtt and his col- 3 de la Mata M, et al. (2003) A slow RNA polymerase II affects through inhibition of RNA polymerase II elongation. Cell 137(4): leagues. In 2009, they presented some of the Mol Cell – alternative splicing in vivo. 12(2):525 532. 708–720. first evidence supporting that chromatin 4 de la Mata M, Kornblihtt AR (2006) RNA polymerase II C-terminal 9 Petrillo E, et al. (2014) A chloroplast retrograde signal regulates structure affects alternative splicing by reg- domain mediates regulation of alternative splicing by SRp20. Nat nuclear alternative splicing. Science 344(6182):427–430. Struct Mol Biol 13(11):973–980. 10 Alló M, et al. (2014) Argonaute-1 binds transcriptional enhancers ulating the speed of transcription (5). The 5 Schor IE, Rascovan N, Pelisch F, Alló M, Kornblihtt AR (2009) and controls constitutive and alternative splicing in human cells. Proc same year, Kornblihtt and his colleagues also Neuronal cell depolarization induces intragenic chromatin Natl Acad Sci USA 111(44):15622–15629.

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