Alberto Kornblihtt

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Kornblihtt at CONICET Alberto Kornblihtt en el stand de CONICET 1.jpg
Kornblihtt at CONICET

Alberto Kornblihtt (born June 30, 1954) is an Argentine molecular biologist who specializes in alternative ribonucleic acid splicing. [1] During his postdoctoral training with Francisco Baralle in Oxford, Kornblihtt documented one of the first cases of alternative splicing, explaining how a single transcribed gene can generate multiple protein variants. Kornblihtt was elected as a foreign associate of the National Academy of Sciences of the United States in 2011, received the Diamond Award for the most relevant scientist of Argentina of the decade, alongside physicist Juan Martin Maldacena, in 2013, [1] and was incorporated to the Académie des Sciences of France in 2022.

Contents

Personal life

Kornblihtt is married, with two adult sons. Outside of his research, Kornblihtt appreciates the opportunity to teach undergraduate biology students at the University of Buenos Aires. In his free time, Kornblihtt enjoys cooking, classical music, numerous genres of literature, etymology, and is a life-long lover of cinema. [2]

Early life and education

Alberto Kornblihtt was born on June 30, 1954, in Buenos Aires, Argentina. [1] His parents taught mathematics and geography, providing Kornblihtt and his two siblings, who also pursued careers in science and education, with an environment for knowledge and learning at an early age. When he was 16 years old, Kornblihtt enrolled in a high school botany and biology class instructed by Rosa Guaglianone, allowing Kornblihtt the opportunity to perform laboratory and microscopy work. This experience launched Kornblihtt's interest in DNA and mRNA. Following high school, Kornblihtt continued his education at the Facultad de Ciencias Exactas y Naturales (School of Sciences) of the University of Buenos Aires, earning a Biology degree in 1977. In 1980, Kornblihtt went on to earn his PhD in biochemistry from Campomar Foundation in Buenos Aires, under the mentorship of Héctor Torres. Kornblihtt then relocated to Oxford, where he held a postdoctoral position from 1981 through 1984 at the Sir William Dunn School of Pathology. Kornblihtt worked with Professor Francisco Barralle during his postdoctoral research, and together, they were successful in cloning the human fibronectin gene. [1] They determined that fibronectin, an important glycoprotein for cell adhesion and tissue repair, [3] was alternatively spliced and could result in the generation of twenty polypeptides. [4]

Research

After completing his postdoctoral research in Oxford, Kornblihtt returned to Argentina in 1984 and accepted a position as an assistant professor of molecular and cell biology at Facultad de Ciencias Exactas y Naturales at the University of Buenos Aires. In 1991 he was appointed full professor and at present he is professor emeritus. Kornblihtt is also a senior CONICET investigator of the CONICET and works with a research team to study the regulation of alternative ribonucleic acid splicing. Alternative splicing occurs during gene expression, allowing exons from a gene to be excluded or included, resulting in a single gene generating multiple proteins. Major projects in Kornblihtt's lab focus on: 1) Coupling transcription with alternative splicing; 2) Alternative splicing and Chromatin; 3) Alternative splicing and spinal muscular atrophy; 4) Ultraviolet light irradiation and alternative splicing; and 5) Alternative splicing in plants. [1] [5]

Research on coupling transcription with alternative splicing

Kornblihtt's lab focuses on the mechanisms that couple transcription with alternative splicing for the regulation of alternative pre-mRNA splicing. Transcription is the process in which a genetic sequence of a gene is transcribed, or changed, from DNA into RNA, to allow for protein production. [6] One of the most significant accomplishments in Kornblihtt's research came in 1997. Kornblihtt's research team was able to an alternative splicing assay combined with promoter swapping to demonstrate that transcription promoters affect the outcome of splicing [7] They later determined that the coupling of transcription and splicing is dependent upon transcriptional elongation speed, or kinetic coupling, and the impact of transcribing RNA polymerase II on splicing. [8] [9] Kornblihtt's research has found that elongation affects alternative splicing events, with slow elongation increasing inclusion of approximately 80% of exons and skipping of approximately 20% in mammalian cells. [5] [10]

More on alternative splicing and chromatin

An additional area of Kornblihtt's study investigated the impact of chromatin structure on alternative splicing. Kornblihtt's research team demonstrated that alternative splicing is impacted by chromatin structure and the rate of transcription. [11] They found that a tighter chromatin structure provides lower rates of elongation and looser chromatin structures provide a higher rate of elongation of transcription. [5] These studies further contributed to the relationship between alternative splicing and epigenetics, which Kornblihtt's team used in studying potential therapies for Skeletal Muscular Atrophy.

Research on alternative splicing and spinal muscular atrophy

Spinal Muscular Atrophy (SMA) is a hereditary degenerative disease of the central nervous system resulting from a spinal motor neuron (SMN) protein shortage. [12] [13] This is due to the deletion or mutation of Survival of Motor Neuron 1 (SMN1). Due to the faulty SMN1 gene, SMA patients do not have enough SMN protein. SMA patients must depend on Survivor of Motor Neurons 2 (SMN2), a gene that all humans have. SMN2 cannot produce sufficient full-length protein for the motor neurons to signal muscles due to sequence differences and the exclusion of exon 7, resulting in the overall SMN protein deficiency. [2] [12] As a treatment strategy for SMA, the first FDA-approved drug, known as Spinraza was developed by Dr. Adrian Krainer and his Cold Spring Harbor Laboratory colleagues. [14] Spinraza is an oligonucleotide that works to activate SMN2 to make more SMN protein in SMA patients. [15] [16] In 2015, the families of Spinal Muscular Atrophy patients encouraged Kornblihtt and Krainer to work together to improve the effectiveness of Spinraza or to develop alternative therapies to be used in conjunction with Spinraza. Kornblihtt's research team focuses on epigenetic strategies, a different mechanism than used Spinraza, to increase SMN protein from the SMN2 gene. [17] Epigenetics studies changes in gene expression, without alteration to the DNA sequence. [18] In 2017 and 2019, Kornblihtt received three separate grants from CURE SMA and FAME (Families of SMA, Argentina) to support continued work on his projects “Epigenetics in SMN2 E7 Alternative Splicing” and “Epigenetics in SMN2 E7 Alternative Splicing II”. [19] [20] In these projects, Kornblihtt's team has worked on the regulation of alternative pre-mRNA splicing to develop new mechanisms for SMN protein development, using a single gene to generate multiple proteins. [19] [20] Kornblihtt's lab continues to work on the SMN2 gene for SMA therapy that focus specifically on exon 7 inclusion to work in conjunction with oligonucleotide treatments, such as Spinraza. [2]

Other research

UV-induced DNA damage

As a continuation of their longterm research on alternative splicing, Kornblihtt's team also studied the impact DNA damage induced by Ultraviolet light (UV) irradiation on alternative splicing in human skin cells. Their research demonstrated that the DNA-damage response to sunlight causes phosphorylation of the RNA polymerase and slowing of the enzyme. Through their research, they found that UV irradiation is necessary to trigger the alternative splicing of many genes and promoting the death of damaged or mutated cells. [21]

Alternative splicing in plants

Adding to their research performed on human cells, Kornblihtt's team expanded their research to study transcription and alternative splicing in plants. The plant Arabidopsis thaliana was used to investigate how external lighting conditions affected alternative splicing. Research showed that the chloroplast, where photosynthesis occurs, senses light and sends a signal to the cell nucleus to regulate alternative splicing. [22] As previously found in mammalian cells, Kornblihtt's team demonstrated that alternative splicing in plants responds to the kinetic coupling mechanism. Their research further showed that light promotes elongation in RNA polymerase II (Pol II) while elongation is lowered in darkness. [22] [23]

Honors and awards

Related Research Articles

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included within or excluded from the final RNA product of the gene. This means the exons are joined in different combinations, leading to different splice variants. In the case of protein-coding genes, the proteins translated from these splice variants may contain differences in their amino acid sequence and in their biological functions.

Trans-splicing is a special form of RNA processing where exons from two different primary RNA transcripts are joined end to end and ligated. It is usually found in eukaryotes and mediated by the spliceosome, although some bacteria and archaea also have "half-genes" for tRNAs.

<span class="mw-page-title-main">SR protein</span>

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

<span class="mw-page-title-main">Spinal muscular atrophy</span> Rare congenital neuromuscular disorder

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.

Gideon Dreyfuss is an American biochemist, the Isaac Norris Professor of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine, and an investigator of the Howard Hughes Medical Institute. He was elected to the National Academy of Sciences in 2012.

An exonic splicing silencer (ESS) is a short region of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the pre-mRNA and contribute to constitutive and alternate splicing. To elicit the silencing effect, ESSs recruit proteins that will negatively affect the core splicing machinery.

<span class="mw-page-title-main">Survival of motor neuron</span> Protein in animal cells

Survival of motor neuron or survival motor neuron (SMN) is a protein that in humans is encoded by the SMN1 and SMN2 genes.

<i>SMN1</i> Protein-coding gene in the species Homo sapiens

Survival of motor neuron 1 (SMN1), also known as component of gems 1 or GEMIN1, is a gene that encodes the SMN protein in humans.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D2</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D2 is a protein that in humans is encoded by the SNRPD2 gene. It belongs to the small nuclear ribonucleoprotein core protein family, and is required for pre-mRNA splicing and small nuclear ribonucleoprotein biogenesis. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified.

<span class="mw-page-title-main">Gem-associated protein 2</span> Protein-coding gene in the species Homo sapiens

Gem-associated protein 2 (GEMIN2), also called survival of motor neuron protein-interacting protein 1 (SIP1), is a protein that in humans is encoded by the GEMIN2 gene.

<span class="mw-page-title-main">NAIP (gene)</span> Protein and coding gene in humans

Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.

<i>SMN2</i> Protein-coding gene in the species Homo sapiens

Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.

<span class="mw-page-title-main">WRAP53</span> Protein-coding gene in the species Homo sapiens

WRAP53 is a gene implicated in cancer development. The name was coined in 2009 to describe the dual role of this gene, encoding both an antisense RNA that regulates the p53 tumor suppressor and a protein involved in DNA repair, telomere elongation and maintenance of nuclear organelles Cajal bodies.

<span class="mw-page-title-main">Epigenetics of neurodegenerative diseases</span> Field of study

Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.

<span class="mw-page-title-main">Nusinersen</span> Medication used for spinal muscular atrophy

Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder.

<span class="mw-page-title-main">Risdiplam</span> Chemical compound

Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA) and the first oral medication approved to treat this disease.

<span class="mw-page-title-main">Adrian Krainer (scientist)</span> Uruguayan neuroscientist

Adrian Robert Krainer is a Uruguayan-American biochemist and molecular geneticist known for his research into RNA gene-splicing. He helped create a drug for patients with spinal muscular atrophy. Krainer holds the St. Giles Foundation Professorship at Cold Spring Harbor Laboratory in Laurel Hollow, New York.

Robin Elizabeth Reed was an American professor of cell biology at the Harvard Medical School. Her research considered the molecular mechanisms that underpin neurodegenerative disease.

<span class="mw-page-title-main">Ravindra N. Singh</span>

Ravindra N. Singh is an Indian American scientist, inventor and academic. He is a professor in the Department of Biomedical Sciences of the College of Veterinary Medicine at Iowa State University.

References

  1. 1 2 3 4 5 6 7 Viegas, J (2015). "Profile of Alberto Kornblihtt". Proceedings of the National Academy of Sciences. 112 (7): 1917–1918. Bibcode:2015PNAS..112.1917V. doi: 10.1073/pnas.1421075111 . PMC   4343084 . PMID   25425664.
  2. 1 2 3 Casadio, M (2017). "Alberto Kornblihtt: Coupling alternative splicing with transcription". Journal of Cell Biology. 216 (2): 284–285. doi: 10.1083/jcb.201701050 . PMC   5294796 . PMID   28104749. S2CID   29616524.
  3. ↑ Yamada, K. M. (2000). "Fibronectin peptides in cell migration and wound repair". The Journal of Clinical Investigation. 105 (11): 1507–1509. doi:10.1172/JCI10119. PMC   300861 . PMID   10841505.
  4. ↑ Kornblihtt, Alberto; Umezawa, K; Vibe-Pederson, K; Baralle, F.E. (1985). "Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene". The EMBO Journal. 4 (7): 1755–1759. doi:10.1002/j.1460-2075.1985.tb03847.x. PMC   554414 . PMID   2992939.
  5. 1 2 3 4 5 6 7 8 9 10 "Regulation of Alternative Splicing". The Kornblihtt Lab. Retrieved March 5, 2021.
  6. ↑ Rabiya (October 5, 2019). "DNA Transcription: Definition, Stages, & Diagram". IBiologia. Retrieved March 6, 2021.
  7. ↑ Cramer, P (1997). "Functional association between promoter structure and transcript alternative splicing". Proceedings of the National Academy of Sciences. 94 (21): 11456–11460. Bibcode:1997PNAS...9411456C. doi: 10.1073/pnas.94.21.11456 . PMC   23504 . PMID   9326631.
  8. ↑ Kornblihtt, Alberto; de la Mata, Manuel; Alonso, Claudio; Kadener, Sebastián; Bentley, David; Cramer, Paula (2003). "A slow RNA polymerase II affects alternative splicing in vivo". Molecular Cell. 12 (2): 525–532. doi: 10.1016/j.molcel.2003.08.001 . hdl: 20.500.12110/paper_10972765_v12_n2_p525_DeLaMata . PMID   14536091.
  9. ↑ Alló, Mariano; Buggiano, Valeria; Fededa, Juan; Petrillo, Ezequiel; Schor, Ignacio; de la Mata, Manuel; Agirre, Eneritz; Plass, Mireya; Eyras, Eduardo; Abou Elela, Sherif; Kornblihtt, Alberto (2009). "Control of alternative splicing through siRNA-mediated transcriptional gene silencing". Nature Structural & Molecular Biology. 16 (7): 717–724. doi:10.1038/nsmb.1620. PMID   19543290. S2CID   205522885.
  10. ↑ Dujardin, Gwendal; Lafaille, Celina; de la Mata, Manuel; Le Jossic-Corcos, Catherine; Corcos, Laurent; Kornblihtt, Alberto (2014). "How Slow RNA Polymerase II Elongation Favors Alternative Exon Skipping". Molecular Cell. 54 (4): 683–690. doi: 10.1016/j.molcel.2014.03.044 . hdl: 11336/32211 . PMID   24793692.
  11. ↑ Schor, I. E. (2009). "Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing". Proceedings of the National Academy of Sciences. 106 (11): 4325–4330. Bibcode:2009PNAS..106.4325S. doi: 10.1073/pnas.0810666106 . PMC   2657401 . PMID   19251664.
  12. 1 2 "About SMA". Spinraza. Retrieved March 7, 2021.
  13. ↑ Cartegni, Luca; Hastings, Michelle; Calarco, John; de Stanchina, Elisa; Krainer, Adrian (2006). "Determinants of Exon 7 Splicing in the Spinal Muscular Atrophy Genes, SMN1 and SMN2". American Journal of Human Genetics. 78 (1): 63–77. doi:10.1086/498853. PMC   1380224 . PMID   16385450.
  14. ↑ Krainer, Adrian (October 23, 2019). "Adrian Krainer elected to National Academy of Medicine". Cold Spring Harbor Laboratory. Retrieved March 7, 2021.
  15. ↑ Chen, Inês (November 19, 2019). "An antisense oligonucleotide splicing modulator to treat spinal muscular atrophy". Nature Portfolio. Retrieved March 7, 2021.
  16. ↑ Marasco, Luciano (November 2019). "El splicing alternativo y la cura de la atrofia muscular espinal". Conicet. 79: 582–586.
  17. ↑ de Barros, Ana (May 30, 2017). "Argentinian Receives Cure SMA Award to Research SMA Epigenetics". SMA News Today. Retrieved March 7, 2021.
  18. ↑ Elnitski, Laura. "Epigenetics" . Retrieved March 7, 2021.
  19. 1 2 3 4 5 "Cure SMA Awards $200,000 Grant to Alberto Kornblihtt, PhD". CureSMA. March 28, 2019. Retrieved March 5, 2021.
  20. 1 2 3 "Cure SMA Awards $140,000 Grant to Alberto Kornblihtt, PhD, Universidad de Buenos Aires, Argentina". Cure SMA. May 15, 2017. Retrieved March 5, 2021.
  21. ↑ Viegas, Jennifer (February 17, 2015). "Profile of Alberto Kornblihtt". PNAS. 112 (7): 1917–1918. Bibcode:2015PNAS..112.1917V. doi: 10.1073/pnas.1421075111 . PMC   4343084 . PMID   25425664.
  22. 1 2 Kornblihtt, Alberto; Godoy Herz, Micaela (March 26, 2019). "Alternative Splicing and Transcription Elongation in Plants". Frontiers in Plant Science. 73: 1066–1074. doi: 10.3389/fpls.2019.00309 . PMC   6443983 . PMID   30972082.
  23. ↑ Godoy Herz, Micaela; Kubaczka, Guillermina; Brzyżek, Grzegorz; Swiezewski, Szymon; Petrillo, Ezequiel; Kornblihtt, Alberto (January 17, 2019). "Light Regulates Plant Alternative Splicing through the Control of Transcriptional Elongation". Molecular Cell. 73 (5): 1066–1074. doi: 10.1016/j.molcel.2018.12.005 . PMID   30661982.
  24. ↑ "Current Fellows". John Simon Guggenheim Memorial Foundation. April 8, 2020. Archived from the original on April 2, 2015. Retrieved March 8, 2021.
  25. ↑ "Howard Hughes Medical Institute Announces Senior International Research Scholars". Philanthropy News Digest. October 2, 2012. Retrieved March 8, 2021.
  26. ↑ "TWAS Awards". United Nations Educational, Scientific, and Cultural Organization. Retrieved March 8, 2021.
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