Research

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Principal Investigator

Mission Statement

Website

Neal Devaraj

One of the major revelations of the Human Genome Project was that protein coding genes comprise only 1.2% of the 3 billion base pairs of the human genome. In contrast, 75% of the genome is transcribed, and most of these transcripts do not code for proteins and are thus classified as noncoding RNAs (ncRNAs). Improved tools for the isolation and imaging of endogenous RNA, and associated protein partners, have the potential to illuminate the various functions and mechanisms of RNA, particularly the vast repertoire of ncRNA elements. Our lab at UCSD has begun developing chemical tools to aid in the imaging and manipulation of RNA. We are approaching this problem by exploiting novel enzymatic and non-enzymatic bioconjugation chemistries. We are applying our novel RNA modifying techniques to study important biological processes, such as RNA-protein interaction, translation, and RNA guided genome editing, etc. We hope our techniques can serve as powerful and versatile tools with applications from basic research in developmental biology and genetics to the development of novel RNA-based therapeutics.

https://www.devarajgroup.com/

Thomas Hermann

Thomas Hermann

We are exploring structured RNA as (1) a drug target and (2) a material to create self-assembling nano-architectures.  

  1. Unique three-dimensional folds enable noncoding RNAs to participate as key players in cellular processes and provide opportunities to develop selective small molecules as inhibitors and modulators of ncRNA function. Ligands that bind selectively to ncRNA targets expand the existing repertoire of protein-directed therapeutics. We use molecular biology and biochemistry to discover and validate RNA targets, biophysical methods to study their structure and discover interactions with ligands, as well as synthetic organic chemistry to prepare and optimize RNA-binding molecules.
  2. Nucleic acid nanotechnology aims to design and build functional materials and devices that self-assemble through base pairing and folding of DNA or RNA strands. We develop crystal structure-guided design and screening approaches to create complex nucleic acid nano-architectures that self-assemble from RNA motifs as architectural joints and DNA building blocks as functional modules for modification and chemical diversification. To obtain complex soft materials, we devise additive and subtractive manufacturing techniques for self-assembling nucleic acid components.
http://tch.ucsd.edu/

lippi_giordano

Giordano Lippi

We are always looking for talented students and post-docs. Come join our team!

We work at the interface between hard-core molecular biology and circuits neuroscience. The goal is to identify the gene programs that build stable neural networks and that allow specific cell types to operate properly within the circuit. In particular, we focus on non-coding RNAs (ncRNAs), a novel and exciting class of regulators of gene expression that emerged during evolution to confer robustness to increasingly complex biological systems. Many ncRNAs are enriched in the brain and increase their expression during development, suggesting that they play fundamental roles in establishing properly balanced neural networks. Consistently, recent literature indicates that changes in ncRNA levels are linked to multiple neurodevelopmental disorders, including autism, schizophrenia and epilepsy. However, how ncRNAs instruct proper neural networks development is not known.  We were the first to show that microRNAs (miRs), a class of ncRNAs, are master regulators of a critical developmental window, during which most synaptic connections are formed. Using an array of techniques, including single unit recording in freely moving animals, calcium imaging, electrophysiology, and behavioral studies, we demonstrated that even a temporary inhibition of specific miRs can trigger profound long-term consequences for network stability and function. The changes include excessive synaptic activity, propensity for seizure-like activity, and memory impairments, recurrent pathological features shared by many neurodevelopmental disorders. Using a set of molecular tools for in vivo dissection of miRs function, we identified and parsed out the molecular pathways regulated by the miRs to achieve a properly balanced network. 
We have now developed a set of genetics tools that will allow us to ask much more sophisticated questions. Which miRs are enriched in different cell-types and what is the specific set of targets they regulate? What are the nodes where regulation of multiple miRs converge and why is redundant regulation necessary? What is the effect of selective removal of miRs from certain cell-types? Are miRs important for the development and function of these cell-types? What are the consequences for network activity and emerging cognitive functions?

https://giordano-lippi-na8a.squarespace.com/

Colleen A. McHugh

We are interested in studying the assembly of non-coding RNA and protein complexes in mammalian cells, particularly long ncRNAs (lncRNAs) associated with human cancers.

Our lab uses a combination of biochemical, biophysical, and genomic tools to identify direct protein interaction partners of lncRNAs and elucidate the molecular structures of lncRNA-protein complexes.

Ultimately, we seek to uncover the mechanisms by which lncRNAs coordinate protein localization and complex assembly, and understand the connection between dysregulation of lncRNA function and cancer progression.

http://mchughlab.ucsd.edu/

Amy E. Pasquinelli

The discovery of miRNA genes in C. elegans and the subsequent recognition that this family of RNAs extends throughout all multicellular organisms has provided researchers with much more than a new class of regulatory RNAs. Although non-coding RNAs have long been appreciated as essential for core biological processes, such as protein translation and mRNA splicing, it is now evident that RNA genes are much more extensive in number and function. The finding that well over half of the human genome is transcribed raises the possibility that non-coding RNA genes may even surpass protein-coding genes in number and perhaps in functional diversity. The recent explosion of interest in RNA-mediated gene regulatory mechanisms is also bolstered by the promise for development of RNA therapeutics to specifically inactivate oncogenes or viruses, for example. This potential depends on basic research aimed at deciphering the elegant regulatory mechanisms evolution has bequeathed to RNA. Thus, a broad goal in the Pasquinelli lab is to contribute experimental evidence towards the general understanding of how regulatory RNAs control gene expression. We hope this knowledge will help elucidate the roles of RNA genes in human health and disease and will provide groundwork for RNA based medical applications. 

http://pasquinellilab.ucsd.edu/

Gene Yeo

A major focus of our lab is to understand how gene expression is controlled at the RNA level to maintain proper functioning of cells during development and aging. Over the past decade, there has been a dramatic increase in the recognition that members of a broad class of proteins termed RNA binding proteins (RBPs) are crucial for maintaining molecular and cellular homeostasis. RBPs regulate processes such as cell survival, pluripotency of embryonic stem cells, and neuronal function, as well as aid in the transition between cellular states in response to stimuli, such as during neural specification of stem cells, cellular stresses, or viral infections.

http://yeolab.github.io

Crystal Zhao

Our laboratory studies the function of (i) RNA modifications and (ii) long noncoding RNAs in stem cells and in cancer biology. 

(i) Like DNA and proteins, covalent chemical modifications have also been reported on messenger RNA (mRNA). In fact, a particular type of mRNA methylation, named N6-methyladenosine (m6A), is highly abundant and tags tens of thousands mRNAs in mammalian cells. Our laboratory is among the first to report heterodimerized METTL3 and METTL14 as the enzymatic complex required for m6A formation. By knocking down or knocking out these enzymes in cultured cells or in mouse models, we demonstrated the requirement of m6A mRNA methylation in regulating embryonic- and neural- stem cell proliferation and self-renewal. Mechanistically, we discovered that the presence of m6A facilitates mRNA decay. In addition, we recently reported a crosstalk between m6A mRNA modification and histone modifications, revealing a novel gene regulatory mechanism in mammalian cells. We are currently investigating mechanisms underlying such crosstalk using neural- and cancer- stem cells as the model systems. 

(ii) In contrast to mRNAs that are translated into proteins, long noncoding RNAs (lncRNAs) do not make proteins, yet are critical for cellular functions. We are particularly interested in a lncRNA named X-inactivation specific transcript (Xist) that is capable of converting an active chromosome into an inactive one. Using CRISPR technology, we recently screened protein factors modulating Xist’s function. We are currently validating and investigating several proteins identified from the screen using mouse embryonic stem cells as a model system. 

Zhao Lab Website

Brian M. Zid

Our group is interested in understanding fundamental properties of gene expression and their effects on the physiology of an organism. We are currently focused on how cells are able to coordinate transcription with translation through differential mRNA localization during stressful conditions. To tackle this problem we use an interdisciplinary approach combining basic biochemistry with next-generation sequencing, quantitative single-cell microscopy, and computational modeling.
http://zidlab.ucsd.edu/

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The San Diego RNA Club is a long running seminar series that engages RNA labs across the San Diego RNA community.

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