Research
The role of cell surface diversity in neural circuit assembly
During brain development, the assembly of functional neural circuits requires mechanisms to connect different neurons. Crucial to this process is the ability of neurites (axons and dendrites) of individual neurons to distinguish between themselves and neurites from other neurons. This mechanism is known as self-avoidance and requires that, in principle, every neuron must express a unique combination of cell-surface recognition molecules to generate a molecular recognition code, i.e. an identity.
The long-term goal of our laboratory is to dissect the molecular mechanisms behind the generation of such code in mammals.
Clustered Protocadherins genes: a code for neural cell-surface diversity
In mammals, the generation of cell-surface diversity requires stochastic and combinatorial expression of a small subset of clustered Protocadherin (Pcdh) genes, randomly chosen from a total of 60. This is a remarkable task especially given that these 60 nearly-identical genes are organized in tandem and are sequestered within a chromatin state, doubly locked by DNA and H3K9 methylation and thus generally refractive to transcription.
At the core of such elegant mechanism for the generation of protein isoform diversity, two fundamental questions remained unanswered: How is random choice of a small number of nearly identical genes achieved? How does localized expression occur in a repressive environment? We use genomic, genetics, biochemical and biophysical approaches to dissect the exquisite coupling between the 3D chromosome architecture, the underlying chromatin structure, transcription and RNA processing that enables the generation of such enormous diversity of molecular identities in neurons.
“The Pcdh gene cluster: an architectural masterpiece” T. Maniatis
Publications
Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons
Science (2024)
Kiefer L.*, Gaudin S.*, Rajkumar S.M., Servito G.I.F., Langen J., Mui M.H., Nawsheen S., Canzio D.
WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring
Science (2023)
Kiefer L.*, Chiosso A.*, Langen J.*, Buckley A.*, Gaudin S., Rajkumar S.M.†, Servito G.I.F.†, Cha E.S., Vijay A., Yeung A., Horta A., Mui M.H., Canzio D.
Cohesin erases genomic-proximity biases to drive stochastic Protocadherin expression for proper neural wiring
bioRxiv (2021)
Kiefer L.*, Servito G.I.F.*, Rajkumar S.M.*, Langen J.*, Chiosso A.*, Buckley A., Cha E.S., Horta A., Mui M.H., Canzio D.
Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin α promoter choice
Cell (2019)
Canzio D., Nwakeze C., Horta A., Rajkumar S., Coffey E., Duffy E., Duffie’ R., Monahan K., O’Keeffe S., Simon M., Lomvardas S., Maniatis T.
Clustered Protocadherin methylation alterations in cancer
Clinical Epigenetics (2019)
Vega-Benedetti A.F., Loi E., Moi L., Blois S., Fadda A., Antonelli M., Arcella A., Badiali M., Giangaspero F., Morra I., Columbano A., Restivo A., Zorcolo L., Gismondi V., Varesco L., Bellomo S.K., Giordano S., Canale M., Casadei-Gardini A., Faloppi L., Puzzoni M., Scartozzi M., Ziranu P., Cabras G., Cocco P., Ennas M. G., Satta G., Zucca M., Canzio D., Zavattari P.
The generation of a Protocadherin cell-surface recognition code for neural circuit assembly
Canzio D., Maniatis T.
Writing, reading, and translating the clustered Protocadherin cell surface recognition code for neural circuit assembly
Mountoufaris G., Canzio D., Nwakeze CL., Chen WV., Maniatis T.
Join the team
Please contact us if you are interested in joining the team.
We are recruiting research assistants, graduate students and postdocs!
Daniele Canzio
Associate Professor
Daniele was born in Rieti, Italy. He received his Bachelor of Science in Biochemistry from the University of California, Santa Barbara and his PhD in Chemical Biology from the University of California, San Francisco under the guidance of Dr. Geeta Narlikar. He then moved to New York City for his postdoctoral training in the laboratory of Tom Maniatis at Columbia University. When not in lab, Daniele loves riding his bike and spending time with Mocha.
Lea Kiefer
Postdoctoral fellow
Lea Kiefer was born and raised near Mannheim, Germany. She moved to the United States to pursue a Bacherlor’s degree in Biochemistry with a minor in Mathematics. She then relocated to the East Coast for graduate school and received her PhD in Molecular Biophysics and Biochemistry from Yale University in 2020 under the guidance of Dr. Matt Simon. Besides her postdoctoral training in the Canzio lab, Lea enjoys the outdoors through hiking and camping.
Jennifer Langen
UCSF, Neuroscience Graduate Student
Jenn was born and raised in Pasadena, a suburb of Los Angeles, CA. She attended the University of Southern California for her undergraduate studies, where she received her B.A. in Neuroscience. Before relocating to the Bay Area as a Neuroscience PhD student, she worked as an undergraduate researcher and lab technician with Dr. Karen Chang at USC. When not thinking about clustered Protocadherins, Jenn keeps herself busy with random artistic pursuits and baking.
Alex Buckley
UCSF, Neuroscience Graduate Student
Alex grew up in the San Francisco Bay Area and went to undergrad at Washington University in St. Louis. He then teched for two years in the lab of Evan Macosko at the Broad Institute before joining the neuroscience program at UCSF. His interest in how neurons acquire their intricate morphologies and wiring patterns drew him to the study of protocadherins. He loves playing tennis, exploring new places, and going on coffee runs with his lab mates.
Carlo Vetralla
UCSF, Tetrad Graduate Student
Carlo was born in Milan, Italy, where he completed his Bachelor’s and Master’s degrees in Medical Biotechnologies. During his thesis, he worked in the Tjian-Darzacq lab at UC Berkeley and later returned to the Bay Area to start a PhD at UCSF in the Tetrad program. In the Canzio lab, he is passionate about enhancer-promoter communication and the dynamics of cohesin loop extrusion in the protocadherin locus. When not in the lab, you can find Carlo in the gym or watching Ac Milan play.
Grace Hala’ufia
UCSF, Neuroscience Graduate Student
Grace joined UCSF as a Neuroscience PhD student in 2023. Born and raised in Marana, Arizona, she stayed in-state to pursue a B.S. in Neuroscience & Cognitive Science at the University of Arizona. There, she worked as an undergraduate researcher studying the behavioral symptoms of neurodegeneration under the mentorship of Dr. Daniela Zarnescu. For her senior thesis, she switched gears and worked with Dr. Arthur Riegel to understand the molecular mechanisms of drug addiction. Outside of the lab, Grace enjoys nature, sports, and playing the viola.
Wendy Cheng
UCSF, Tetrad Graduate Student
Wendy was born and raised in Shenzhen, China. She moved to the UK to study biological natural sciences at the University of Cambridge. Her summer internships at Tsinghua University and MRC LMB led to her interest in phase-separated condensates, and for her thesis in the Genetics Department, she simulated phase separation in silico to learn more about their roles in 3D genome organization. She is always willing to discuss about cats (and of course science).
Jaden Lucas-Retherford
Research Assistant
Jaden is a chemist.
Michael Mui
Research Assistant
Michael was born in Hong Kong and was raised in San Francisco, CA. He received his B.S. in Animal Science from UC Davis. Prior to joining the Canzio lab, he was an animal technician at UCSF. Michael is joined between the Canzio and the Paredes labs at UCSF. When not in lab, Michael likes to watch movies, draw, and spend time with his dog.
Mocha
Fluffy friend
Mocha is a New Yorker. Prior to joining the Canzio lab she “worked” as a happy doggie in Daniele’s house.
Lab Alumni
Sandy Rajkumar (PhD student in Biochemistry, Cell & Molecular Biology, Weill Cornell)
Gabrielle Servito (PhD student in Chemical Biology, Biochemistry, & Biophysics, UC Santa Cruz)
Lisa Cha (MD/PhD student, UCLA)
Anna Chiosso (PhD student in Neuroscience, University of Zurich)
Akshara Vijay (Research Technician, Weill Cornell)
Albert Yeung (Research Technician, University of Pennsylvania)
Simon Gaudin (PhD student in Genetics, Stanford)
Find us
UCSF Weill Institute for Neurosciences
1651 4th Street, 4th floor
San Francisco, CA, 94158, USA
Department of Neurology
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Dep of Biochemistry & Biophysics
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Dep of Psychiatry
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