The role of cell surface diversity in the assembly of neural circuits
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 themselvesand 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 a cell-surface diversity code for neural self-avoidance requires stochastic and combinatorial expression of only 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
Canzio D., Maniatis T. The generation of a protocadherin cell-surface recognition code for neural circuit assembly. Curr Opin Neurobiol. 2019 Dec;59:213-22-. PMID: 31710891.
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. Clustered protocadherins methylation alterations in cancer. Clinical Epigenetics, 2019 Jul 9;11(1):100
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. Antisense lncRNA transcription mediates DNA demethylation to drive stochastic Protocadherin a promoter choice. Cell, 2019 Mar 30. pii: S0092-8674(19)30270-3
Mountoufaris G., Canzio D., Nwakeze CL., Chen WV., Maniatis T. Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly. Annual Rev Cell Dev Biol. 2018 Oct 6;34:471-49
Duffy EE., Canzio D., Maniatis T., Simon MD. Solid phase chemistry to covalently and reversibly capture thiolated RNA. Nucleic Acids Res. 2018 Aug 21;46(14):6996-7005
Guo Y., Xu Q., Canzio D., Shou J., Li J., Gorkin DU., Jung I., Wu H., Zhai Y., Tang Y., Lu Y., Wu Y., Jia Z., Li W., Zhang MQ., Ren B., Krainer AR., Maniatis T., Wu Q. CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function. Cell. 2015 Aug;162(4):900-10
Canzio D., Larson A., Narlikar G.J.Mechanisms of functional promiscuity by HP1 proteins. Trends in Cell Biology. 2014 Jun; 24(6):377-86
Canzio D., Liao M., Naber N., Pate E., Larson A., Wu S., Marina D.B., Garcia J.F., Madhani H.D., Cooke R., Schuck P., Cheng Y., Narlikar G.J.A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature. 2013; 496(7445):377-81
Canzio D., Chang E.Y., Shankar S., Kuchenbecker K.M., Simon M.D., Madhani H.D., Narlikar G.J., Al-Sady B.Chromodomain mediated oligomerization of HP1 suggests a nucleosome bridging mechanism for heterochromatin assembly. Molecular Cell. 2011; 41(1), 67-81
Armache K.J., Garlick J.D., Canzio D., Narlikar G.J., Kingston R.E. Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 Å resolution. Science. 2011; 334(6058); 977-82
Park M., Canzio D., Bruice T.C. Incorporation of positively charged ribonucleic guanidine linkages into oligodeoxyribonucleotides: development of potent antisense agents. Bioorg Med Chem Lett. 2008; 18(7), 2377-84
Correa B.J., Canzio D., Kahane A.L., Reddy P.M., Bruice T.C. DNA sequence recognition by Hoechst 33258 conjugates of hairpin pyrrole/imidazole polyamides. Bioorg Med Chem Lett. 2006; 16(14), 3745-50
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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.
Sandy M. Rajkumar
Sandy was born in Coimbatore, India. She received her Bachelor of Science in Biotechnology from Domodaran College, India and her Master of Science in Biological Science from University of Massachusetts Lowell. Prior to joining the Canzio lab, she worked as a Research Associate in Moderna Therapeutics and as a Staff Associate in the Maniatis lab at Columbia University.
Gabrielle Isabelle Servito
Gabrielle (Gabby) was born in Vallejo, California. She received her Bachelor of Science in Chemistry with a concentration in biochemistry from the University of San Francisco. Prior to joining the Canzio lab, she worked as an undergraduate researcher in the Yang lab at the University of San Francisco.
Mocha is a New Yorker. Prior to joining the Canzio lab she “worked” as a happy doggie in Daniele’s house.
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