- Assistant Professor of Genetics & Development
I grew up in the beautiful city of Palermo, in southern Italy. I used to spend hours exploring the countryside and observing animal life. I was curious about everything then, and I still am.
During my doctoral studies at the TIGEM in Italy, in the lab of Sandro Banfi, my first publication was in the microRNA field. MicroRNAs (miRNAs) are small molecules that regulate the function of most human genes; the challenge has been to identify each miRNA’s set of target genes. Various bioinformatic methods had been tried, but each approach reveals a different set of targets for a given microRNA. I took a different tack: I hypothesized that the target genes of a given miRNA are likely to belong to the same biological pathway and therefore to be co-expressed. This basic idea led me to develop HOCTAR (Genome Research, 2009) and then the more refined CoMeTa (Genome Research, 2012), whose prediction accuracy reaches nearly 100%, as calculated by analysis of previously characterized human miRNAs. CoMeTa was the first tool to infer the biological pathways of each human miRNA based on the identification of its set of target genes. HOCTAR led to the discovery of the function of miR-128, which controls the master gene TFEB (Science, 2009).
For my postdoctoral work I wanted to bring my background in bioinformatics and RNA biology to bear on problems in neuroscience, so I joined the lab of Huda Zoghbi. I studied the regulation of the epigenetic factor MECP2 during neurodevelopment (Genes & Development, 2013), the post-translational modification of a neurodegenerative disease protein, Ataxin1 (Cell, 2015 and Cell, 2018), and alternative polyadenylation (eLife, 2015). This work forms the basis of my lab’s current projects.
Neuroscience made enormous strides during the 1990’s with the advent of molecular genetic techniques that allowed us to identify myriad disease genes and manipulate them in animal models from flies to mice. In the 2000’s, we came to appreciate the importance of epigenetic mechanisms to neurobiology, and now we are on the cusp of a new field that might be called “RNA neurobiology.”
RNA biology may, in fact, have particular importance in the brain, given the extremely dynamic nature of neuronal synapses. The post-synaptic compartment contains polysomes, which indicates that translation is crucial for higher-order brain activity, and protein synthesis has long been thought to be required for memory consolidation. Small wonder, then, that disruption of RNA-binding proteins is associated with wide-ranging syndromes that affect motor control, behavior, and cognition.
My interest in RNA-binding proteins centers on their role in post-transcriptional regulation of proteins that, when mutated, lead to human neurological disease. But my interest is in the wild-type versions of these proteins: my research has shown that relatively modest increases or decreases in the levels of at least some ‘normal’ proteins can be pathogenic. This opens up an entirely new avenue to discovering new neurological disease genes, as I showed recently in the identification of patients bearing mutations in Pumilio1 (Cell, 2018).
Departments and Divisions
- Department of Genetics & Development
Education and Training
- MS, 2005 Biological Sciences, University of Palermo, Faculty of Medicine (Italy)
- PhD, 2009 Medical Genetics, Second University of Naples (Italy)
- Fellowship: 2006 University of Milan (Italy)
Hammer Health Sciences Building701 West 168th Street
New York, NY 10032
- (212) 305-7863
- Lab Phone:
- (212) 305-6133
2010-2017 Postdoctoral Associate, lab of Huda Zoghbi, MD, Department of Molecular and Human Genetics at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas.
2006-2009 Doctoral student, lab of Sandro Banfi, MD at the Telethon Institute of Genetics and Medicine (TIGEM) and School of Medicine of Second University of Naples (SUN), Italy.
2005-2006 Bioinformatics Research Fellow, lab of Elia Stupka, PhD at TIGEM, Naples, in collaboration with Graziano Pesole, University of Milan.
2005 Molecular Biology Fellow, lab of Fabrizio Vitale, D.V.M., at the Instituto Zooprofilattico Sperimentale della Sicilia (IZSS) of Palermo, Italy.
2003-2005 Undergraduate student researcher in the laboratories of Fara Misuraca, PhD (Department of Biology and Development University of Palermo) and Fabrizio Vitale, D.V.M. (IZSS).
Global Health Countries
- United States
Honors and Awards
- Paul A. Marks Scholar, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
- “Hot chair” travel award (invited speaker) to the 7th Ataxia Investigators Meeting (AIM), April 1-5, Philadelphia, PA
- Young Investigator Research Grant 2018. “Delineating the PUM1 functional network in mice and humans.” The National Ataxia Foundation.
- NARSAD Young Investigator Award 2018. “PUMILIO1 mutations cause two new neurological disorders: understanding its role in Mice and Humans.” The Brain & Behavior Research Foundation.
- Young Investigator Research Grant 2017. “PUMILIO1 deficiency: understanding a new ataxia gene and its role in cerebellar dysfunction in mice and humans.” The National Ataxia Foundation.
- Best Speaker Prize, 6th Ataxia Investigators Meeting (AIM) at Caribe Royale, April 1, Orlando, Florida.
- “Hot Chair” travel award to attend the 6th Ataxia Investigators Meeting (AIM) at Caribe Royale, March 29-April 1, Orlando, Florida.
- First prize, “Best Paper” in the Department of Molecular and Human Genetics, Baylor College of Medicine Retreat, January 14-15, Galveston, TX.
- Winner, “Scientific Storytelling” Pediatric Research & Fellows’ Symposium, March 26, Department of Pediatrics, Texas Children’s Hospital, Houston, TX.
- Received National Scientific Qualification as Associate Professor in Experimental Biology, Ministry of Education, Universities and Research (MIUR).
- Young speaker special selection invitation to Keystone Symposia on Molecular and Cellular Biology – The Biology of RNA Silencing Meeting, April 25-30, Victoria British Columbia, Canada.
- One of 150 applicants selected to attend “Advanced Topics in Molecular Medicine,” July 15-18, at AREA Science Park (CBM-CEI) in Trieste, Italy.
- One of 100 applicants selected to attend the Accademia Nazionale dei Lincei Meeting, “The world of small non-coding RNAs,” June 11-12, Rome, Italy.
- Early Researcher Career Development Award provided by the Italian Ministry of Education, Universities and Research (MIUR) at the University of Milan; I am the only student (so far) to have won twice.
- Developing RNA therapeutic approaches to neurological diseases
- Establishment and maintenance of RNA homeostasis in the brain
- Protein dosage and neurological disorders
- RNA-binding proteins and non-coding RNA regulatory networks in neurological disorders
“Deciphering the role of Pumilio1 in two new neurological diseases” R01 NS109858-01A1. Source: NINDS. Total funding: $2,198,845 over five years. Role: Principal Investigator.
Paul A. Marks Scholar Program, Columbia University Vagelos College of Physicians and Surgeons. $300,000 over three years.
Brain & Behavior Research Foundation, NARSAD Young Investigator Award. “PUMILIO1 mutations cause two new neurological disorders: understanding PUM1 function in mice and humans.” Role: PI. $70,000 over two years.
National Ataxia Foundation Young Investigator Research Award (Jan 1 to Dec 31, 2018). “Delineating the PUM1 functional network in mice and humans.” Role: PI. $35,000 for one year.
National Ataxia Foundation Young Investigator Research Award (Jan 1 to Dec 31, 2017). “PUMILIO1 deficiency: understanding a new ataxia gene and its role in cerebellar dysfunction in mice and humans.” Role: PI. $35,000 for one year.
DECIPHERING THE ROLE OF PUMILIO1 IN TWO NEW NEUROLOGICAL DISEASES (Federal Gov)
Jun 15 2019 - Mar 31 2024
DIETARY CONTRIBUTION IN CEREBELLAR ATAXIA (Federal Gov)
Sep 15 2019 - Aug 31 2021
BRAIN & BEHAVIOR RESEARCH FOUNDATION NARSAD 2017 YOUNG INVESTIGATOR AWARD (Private)
Jan 15 2018 - Jan 14 2020
DELINEATING THE PUM1 FUNCTIONAL NETWORK IN MICE AND HUMANS (Private)
Jan 1 2018 - Dec 31 2018
We currently have two main projects. The first stems from our discovery that mutations in Pumilio1 (PUM1), an RNA-binding protein, cause a neurodegenerative disease reminiscent of spinocerebellar ataxia type 1 (SCA1). We discovered that PUM1 negatively regulates ATXN1 levels and is also necessary for normal neurodevelopment. In mice, Pum1 deficiency increases WT Atxn1 mRNA and protein levels by about 40%. Removing a copy of Atxn1 in these mice reduces SCA1-like pathology by normalizing WT Atxn1 levels (Cell, 2015). This led us to propose that PUM1 mutations in humans would also cause disease, and we have found that in humans, PUM1 mutations actually cause two distinct diseases, one neurodevelopmental, and one neurodegenerative (Cell, 2018).
The second project builds on our discovery that the CFIm protein complex regulates MeCP2 protein levels. MECP2, the gene mutated in Rett syndrome, is peculiar for having a very long (~8.5 kb) 3’UTR that contains two prominent poly-adenylation (p(A)) sites: a proximal p(A) and a distal p(A), resulting in short and long messenger mRNA isoforms, respectively. Through alternative polyadenylation (APA), a gene can give rise to multiple mRNA isoforms of their 3’UTRs, allowing them to be acted upon by post-transcriptional regulatory factors such miRNAs and RBPs. We identified eleven individuals with neuropsychiatric disease who have copy number variations (CNVs) spanning NUDT21 (CFIm25), which regulates MeCP2 protein levels by APA sites in the MECP2 3’UTR. These individuals suffer from autism spectrum disorder and notable developmental regression, very similar to Rett Syndrome. We thus discovered that NUDT21 duplication is a cause of neuropsychiatric disease along the autism spectrum (eLife, 2015). We are expanding our studies to identify the role of the CFIm complex in other human neurological diseases.
- Alexei Chemiakine, Senior Research Technician
Gennarino VA†, Palmer EE, McDonell LM, Wang L, Adamski CJ, Koire A, See L, Chen CA, Schaaf CP, Rosenfeld JA, Panzer JA, Moog U, Hao S, Bye A, Kirk EP, Stankiewicz P, Breman AM, McBride A, Kandula T, Dubbs HA, Macintosh R, Cardamone M, Zhu Y, Ying K, Dias KR, Cho MT, Henderson LB, Baskin B, Morris P, Tao J, Cowley MJ, Dinger ME, Roscioli T, Caluseriu O, Suchowersky O, Sachdev RL, Lichtarge O, Tang J, Boycott KM, Holder JL, and Zoghbi HY†. "A mild PUM1 mutation is associated with adult-onset ataxia, whereas haploinsufficiency causes developmental delay and seizures." Cell, 2018 Feb 22;172(5):924-936e.11. (†Corresponding authors).
Gennarino VA*, Alcott CA*, Chen CA, Chaudhury A, Rosenfeld JA, Parikh S, Wheless JW, Roeder ER, Horovitz DDG, Roney EK, Smith JL, Cheung SW, Li W, Nailson JR, Schaaf CP, Zoghbi HY. "NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation." eLife, 2015 Aug 27;4. doi: 10.7554/eLife.10782. (*Contributed equally).
Gennarino VA, Singh RK, White JJ, De Maio A, Han K, Kim JY, Jafar-Nejad P, di Ronza A, Kang H, Sayegh LS, Cooper TA, Orr HT, Sillitoe RV and Zoghbi HY. "Pumilio1 Haploinsufficiency Leads to SCA1-like Neurodegeneration by Increasing Wild-Type Ataxin1 Levels." Cell, 2015 Mar 12;160(6):1087-98. This paper was highlighted in an ALZ forum press release.
Han K*, Gennarino VA*, Lee Y, Pang K, Hashimoto-Torii K, Choufani S, Raju CS, Oldham MC, Weksberg R, Rakic P, Liu Z, and Zoghbi HY. "Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p." Genes & Development, 2013 Mar 1;27(5):485-90. (*Contributed equally). This paper was selected for the journal cover.
Gennarino VA, D'angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, Mutarelli M, Belcastro V, Ballabio A, Verde P, Sardiello M, Banfi S. "Identification of microRNA-regulated gene networks by expression analysis of target genes." Genome Research, 2012 Jun;22(6):1163-72. Epub 2012 Feb 24.
Gennarino VA, Sardiello M, Avellino R, Meola N, Maselli V, Anand S, Cutillo L, Ballabio A and Banfi S. "MicroRNA target prediction by expression analysis of host genes." Genome Research, 2009 Mar;19(3):481-90. Epub 2008 Dec 16.
For a complete list of publications, please visit PubMed.gov