Breadcrumb

Joana A. Vidigal

Joana A. Vidigal, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
NIH Distinguished Scholar

RESEARCH SUMMARY

Our long-term goal is to understand the mechanisms through which small noncoding RNA pathways regulate gene expression during animal development, tissue homeostasis, and disease. Our work relies on the use of mouse models and genetic tools, together with biochemical and computational approaches, to stringently define the requirement of these pathways in vivo. Ultimately, we aim to gather actionable knowledge that can be used to design better strategies for screening, prevention, and treatment of human diseases.

If you are interested in your work, find out how to join us!

Areas of Expertise

Small RNA Pathways
Noncoding RNAs
Mouse Genetics and Genome Editing

Publications

Selected Publications

AGO2 silences mobile transposons in the nucleus of quiescent cells

Laura Sala, Srividya Chandrasekhar, Rachel L. Cosby, Gaspare La Rocca, Todd S. Macfarlan, Parirokh Awasthi, Raj Chari, Michael Kruhlak, Joana A. Vidigal
bioRxiv . 2022.
Full-Text Article

CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens

Perez AR, Sala L, Perez RK, Vidigal JA.
Nature Communications. 2021.
Full-Text Article
[ Journal Article ]

AGO Unchained: Canonical and non-canonical functions of mammalian Argonaute proteins

Sala L, Chandrasekhar S, Vidigal JA
Frontiers in Biosciences. 2020.
Full-Text Article
[ Journal Article ]

GuideScan software for improved single and paired CRISPR guide RNA design

Perez AR*, Pritykin Y*, Vidigal JA*#, Chhangawala S, Leslie CS#, and Ventura A#
Nature Biotechnology. 35(4): 347-349, 2017. [ Journal Article ]

An allelic series of miR-17~92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron

Han YC*, Vidigal JA*, Mu P*, Yao E, Singh I, González AJ, Concepcion CP, Bonetti C, Ogrodowski P, Carver B, Selleri L, Betel D, Leslie C, and Ventura A.
Nature Genetics. 47(7): 766-75, 2015. [ Journal Article ]

Job Vacancies

We have no open positions in our group at this time, please check back later.

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Team

Mahendra Prajapat
Postdoctoral Fellow (Visiting)
Mahendra Prajapat, Ph.D.
Manish Kumar
Postdoctoral Fellow (Visiting)
Manish Kumar, Ph.D.
Alex Perez
Special Volunteer
Alexander Perez, Ph.D.
Contractor (Technician)
Andrea Gutierrez Maria
Pre-doctoral IRTA (Graduate Student)
Aurelia Moses

News

**New paper alert!** AGO2 regulates young transposons in the nucleus of Quiescent Cells

Argonaute proteins are key cytoplasmic components of the miRNA pathway, with critical roles in animal development and disease. Although studies have suggested that their functions can be regulated, we do not currently understand in which physiological contexts that happens or what purpose it serves. We have generated a mouse model with an epitope tag at the endogenous Argonaute 2 (Ago2) locus allowing us to address this question for the first time in vivo. In our initial characterization of Ago2HA/HA mice (Sala, 2022) we found that in quiescent cells, the repressive roles of AGO2 are diverted away from post-transcriptional regulation of mRNAs in the cytoplasm via the miRNA pathway to instead co-transcriptionally repress mobile transposons in the nucleus via its conserved—but poorly understood—catalytic domain.

We believe this study describes a significant advancement to the field:

  • It changes our view of mammalian AGO2, from a protein with ubiquitous cytoplasmic functions in the miRNA pathway to one whose functions can be switched between two regulatory modes in a binary fashion that depends on cellular state. In fact, AGO2 localization is regulated by the Pi3K-AKT-mTOR pathway (an established regulator of cell cycle entry and exit) and is mechanistically linked to down-regulation of miRNA pathway components;
  • Our finding that in the nucleus of quiescent cells AGO2 associates with chromatin where it represses young retrotransposons via its catalytic domain also overturns the long-held assumption in the field that in vertebrates, RNAi occurs exclusively in the context of mouse oocytes. Direct cleavage of transposon RNA by cytoplasmic AGO2 in murine oocytes is possible in part due to the absence of an active interferon signaling whose dominance in other cellular contexts has been shown to compete with and prevent RNAi. In contrast to this long-standing model, our work provides evidence—the first to our knowledge—of the existence of RNAi in the soma of mammals. As in the murine germline, repression of transposon expression in quiescence likely protects the genome of these long-lived cells against mobile elements whose mutagenic potential can be catastrophic not only to the cell itself, but also the organ it resides in, and ultimately the organism. In contrast to the germline however, RNAi in the soma seems to be achieved through the re-localization of AGO2 to the nucleus, a phenomenon that may prevent direct competition with the cytoplasmic sensors and effectors of the interferon pathway.

Thus, our work reveals a previously unrecognized but essential regulatory mechanism, shows that in somatic cells AGO2’s functions in the miRNA or RNAi pathways are spatially segregated, and provides a compelling physiological requirement for the retention of a catalytic competent AGO protein in the vertebrate genome.

We are actively searching for Postdocs/PhD students interested in helping us further characterize the roles of AGO2 in the nucleus of quiescent cells.

Alumni

Andy Saiz
Andy Saiz
06/2020-06/2022
moved on to: PhD at MIT
Naheel Khatri
Naheel Khatri
08/2020-08/2022
moved on to: MD/PhD at Stony Brook
Nithya Chintalapati
Nithya Chintalapati
07/2020-09/2021
Michael Chang
Michael Chang
07/2019-07/2020
moved on to: MD at Hopkins
Srividya Chandrasekhar
Srividya Chandrasekhar
08/2018-08/2020
moved on to: PhD at Berkeley
Stephen Moore
Stephen Moore
09/2018-08/2019
moved on to: PhD at University of Buffalo