A member of the National Academy of Sciences, Dr. Rao received her undergraduate and master’s degrees from Osmania University in India and her Ph.D. from Harvard University. After many years as a faculty member at the Harvard Medical School and the Immune Disease Institute in Boston, she joined the La Jolla Institute in 2010. She has worked on signaling and gene transcription for many years, is a member of numerous advisory panels, and has received several major awards.
Our research has been focused on understanding how signalling pathways control gene expression, using T cells and other cells of the immune system as models. There are several aspects to our research. We are particularly interested in a pathway of gene expression that is regulated by calcium influx into many different types of cells: it involves a process known as store-operated calcium entry, which activates a phosphatase, calcineurin, which dephosphorylates and sends a transcription factor, NFAT, to the nucleus. NFAT turns on a large number of genes, in a manner appropriate to the cell type and mode of stimulation; in T cells, it controls both the positive transcriptional programmes of T cell activation and negative programmes known as anergy or exhaustion that attenuate T cell activation. We are using RNA interference and CRISPR/Cas9 screens, mice with targeted gene disruption, high-throughput sequencing and other technologies to analyze how genes are regulated and how loss of function of certain proteins leads to diseases such as autoimmunity, immune deficiencies, developmental defects and cancer. A current important focus involves the TET family of 5-methylcytosine oxidases, which control cell lineage specification in many different systems. Profound TET loss-of-function is associated with aggressive cancers, both in human and in mouse model systems, and we are examining the mechanisms involved.
From The Lab
Exhausted T cells
Dual loss of TET proteins prompts lethal upsurge in inflammatory T cells in a mouse model of lymphoid cancer
TET proteins drive early neurogenesis
TET proteins help maintain genome integrity
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia
TET proteins in natural and induced differentiation
Transcriptional and epigenetic regulation of T cell hyporesponsiveness
TET2 regulates mast cell differentiation and proliferation through catalytic and non-catalytic activities
Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis
Lineage-specific functions of TET1 in the postimplantation mouse embryo
Lineage-specific functions of TET1 in the postimplantation mouse embryo
The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection
TET family dioxygenases and DNA demethylation in stem cells and cancers
Precancer atlas to drive precision prevention trials
TET methylcytosine oxidases in T cell and B cell development and function
Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells
TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells
Leveraging premalignant biology for immune-based cancer prevention
DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
LuxGLM: a probabilistic covariate model for quantification of DNA methylation modifications with complex experimental designs
A probabilistic generative model for quantification of DNA mudifications enables analysis of demethylation pathways
Cutting edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection
DNA methylation and hydroxymethylation in hematologic differentiation and transformation
TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling
Acute loss of TET function results in aggressive myeloid cancer in mice
Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis
Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex
The histone deacetylase SIRT9 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine
RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation
Store-operated calcium entry: mechanisms and modulation
A zerbrafish model of myelodysplastic syndrome Produced through tet2 genome editing
TET proteins and 5-methylcytosine oxidation in hematological cancers
Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in coprinopsis cinerea
Connections between TET proteins and aberrant DNA modification in cancer
In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation
Jarid2 is induced by TCR signalling and controls iNKT cell maturation
Epigenomic analysis of primart human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility
Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation
Halofuginone-induced amino acid starvation regulates stat3-dependent th17 effector function and reduces established autoimmune inflammation
Lineage-specific expansions of TET/JBP genes and a new class of DNA transposons shape fungal genomic and epigenetic landscapes
Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells
Large conserved domains of low DNA methylation maintained by Dnmt3a
ORAI1 calcium channel orchestrates skin homeostasis
MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation
T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia
Vitamin C induces tet-dependent DNA demethylation and a blastocyst-like state in ES cells
Global epigenomic reconfiguration during mammalian brain development
Initial activation of STIM1, the regulator of store-operated calcium entry
An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry
TETonic shift: biological roles of TET proteins in DNA demethylation and transcription
Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX
Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry
DNA methylation and methylcytosine oxidation in cell fate decisions
Stage-specific roles for tet1 and tet2 in DNA demethylation in primordial germ cells
High-resolution nucleosome mapping ot targeted regions using BAC-based enrichment
TET proteins and 5-methylcytosine oxidation in the immune system
Nurr'ishing treg cells: Nr4a transcription factors control Foxp3 expression
O-GlcNAcylation and 5-methylcytosine oxidation: an unexpected association between OGT and TETs
T cell activation indiuces proteasomal degradation of argonaute and rapid remodeling of the micro RNA repertoire
PGC7, H3K9me2 and Tet3: regulators of DNA methylation in zygotes
New functions for DNA modifications by TET-JBP
Immunoloty. Cooperative transcription factor complexes in control
Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells
The anti-CMS technique for genome-wide mapping of 5-hydroxymethylcytosine
The GLIB technique for genome-wide mapping of 5-hydroxymethylcytosine
Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors
D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
Nontargeted nucleotide analysis based on benzoylhistamine labeling-MALDI-TOF/TOF-MS
RNA-binding protein L1TD1 interacts with LIN28 via RNA and is required for human embryonic stem cell self-renewal and cancer cell proliferation
Halofuginone and othe rfebrifugine derivatives inhibit prolyl-tRNA synthetase
RNA binding protein L1TD1 interacts with LIN28 via RNA and is required for human embryonic stem cell self-renewal and cancer cell proliferation
Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2 and DNMT3A
TET2: an epigenetic safeguard for HSC
Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice
Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex
Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells
Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells
Interaction of calcineurin with substrates and targeting proteins
Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells
Edahi Gonzalez Avalos
Joyce Chen received her BS in Biochemistry from the University of California, Los Angeles (UCLA). She then worked as a research associate at the California Institute of Technology (Caltech) in the laboratory of Dr. David Baltimore, where she helped develop an adeno-associated virus (AAV)-based HIV prophylaxis. Currently, Joyce is a MD/PhD student at the University of California, San Diego (UCSD), and she is doing her thesis work in the laboratory of Dr. Anjana Rao at the La Jolla Institute for Allergy and Immunology.
Joyce is working to elucidate the roles of these transcription factors in CD8 T cell exhaustion.
Benjamin Delatte is an HHMI fellow from the Jane Coffin Childs foundation. He has performed his Ph.D training in Prof. François Fuks’ laboratory in Belgium at the time that TET function was discovered by the team of Dr. Anjana Rao. Applying proteome and genome-wide approaches, he found that the most potent partner of TETs is the glycosyltransferase OGT (Deplus*, Delatte* et al., Embo, 2013), and recently discovered that Tet is responsible for RNA hydroxymethylation in drosophila (Delatte et al., Science, 2016).
Ben is now investigating the roles of TETs and hydroxymethylcytosine in genomic instability and cancer. He is also developing novel methodologies to map epigenetic modifications, and to identify diverse hallmarks of cancer such as DNA breaks or aberrant DNA:RNA structures
Marlet Morales Franco
Research Technician I
Xiang Li received his undergraduate degree from Nanjing University in 2005. From there, he proceeded to receive his Ph.D. in Stem Cell Research and Developmental Biology at the Institute of Health Sciences at the Chinese Academy of Sciences in Shanghai, China in 2011. Xiang Li’s is currently an instructor in Dr. Anjana Rao’s lab at the La Jolla Institute for Allergy and Immunology.
Xiang Li’s research is focused on the role of Tet family in cardiac and neural cell fate determination in mouse embryonic stem cells.
Chan-Wang (Jerry) Lio
Jerry Lio received his undergraduate and master’s degree in Microbiology and Immunology at National Yang-Ming University in Taiwan. Mentored by Dr. Chyi-Song Hsieh, he later obtained his Ph.D. from Washington University in St. Louis with a focus on the thymic development of Foxp3+ regulatory T cells. Currently he is an instructor at Dr. Anjana Rao’s lab at La Jolla Institute for Allergy and Immunology.
Jerry’s research focuses on understanding the roles of TET proteins and DNA cytosine hydroxymethylation in the function and transformation of B cells.
Isaac F. López-Moyado received his B.S. in Genomic Sciences from the National Autonomous University of Mexico (UNAM), and completed his undergraduate degree while doing research in the laboratory of Walter Fontana at Harvard Medical School (HMS) where he worked on aging in C. elegans and lifespan distributions. After graduating from UNAM, Isaac started his Ph.D. in the Bioinformatics and Systems Biology program at the University of California, San Diego (UCSD), where he is mentored by Dr. Anjana Rao.
Isaac’s research focuses on the role of TET proteins and oxidized methylcytosines in maintaining genome integrity, and their relationship to oncogenesis.
I graduated from the University of Tokyo in 2002 with a Bachelor of Science degree in Chemistry and Biotechnology. I then moved to Chiba University, School of Medicine, and finished M.D.-Ph.D. course in 2010. Directly after that, I began working as an Assistant Professor at the Chiba University, Graduate School of Medicine. In 2016, I got an Associate Professor positon in the Global Prominent Research Institute at Chiba University, which promotes international collaboration between the University of California, San Diego (UCSD) and Chiba University. That is one of the reasons I began working as a Postdoctoral Fellow at the La Jolla Institute for Allergy and Immunology (LJI) in July of 2017.
For the past several years my research has been focused on the study of the epigenetic regulation of T-cells in the context of their functions in the immunological memory. Particularly, Polycomb and Trithorax proteins, which methylate histone H3-K27 and K4, respectively, have been of interest to me. In the LJI, I will study the roles of 5-hydroxymethylcytosine (5hmC) in T-cell-mediated immune responses, mainly focusing on its role in DNA demethylation.
Goals in my career in scientific research are as follows:
1. Clarify the molecular basis of the immunological memory.
2. Induce general principles or laws from big data (e.g. next generation sequencing).
3. Apply the knowledge acquired from the basic research to the treatment of intractable diseases.
Vipul Shukla received his undergraduate degree in Zoology from the University of Delhi in New Delhi, India in 2007, and then proceeded to receive his master’s degree in Toxicology from Jamia Hamdard University in New Delhi, India in 2009. He later obtained his Ph.D. from the University of Nebraska Medical Center in Omaha, Nebraska in 2016 with a focus on Genetics, Cell Biology and Anatomy. Currently, he is a postdoc in Dr. Anjana Rao’s lab at La Jolla Institute for Allergy and Immunology.
Vipul’s research focus is on investigating the role of TET proteins as regulators of genomic stability.
I received my bachelor in Biology from the National and Kapodistrian University in Athens Greece and my PhD in Immunology from the Aristotle university of Thessaloniki in Greece. I joined the Rao lab in the La Jolla Institute in November and 2010 and was promoted to Instructor in 2013.
I am working on the regulation of gene expression in T cell development. My aim is to dissect how aberrations of the differentiation process can result in autoimmunity or malignant transformation and cancer emergence.
Xiaojing received her undergraduate degree from Jilin University in Changchun, China in 2004, and then proceeded to obtain her master’s from the Institute of Microbiology at the Chinese Academy of Sciences in Bejing, China in 2007. Then in 2011, she received her Ph.D. in Immunology under the mentorship of Dr. Tilman Borggrefe from the Max-Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany. Currently, she is an instructor in Dr. Anjana Rao’s lab at La Jolla Institute for Allergy and Immunology.
Xiaojing’s research focuses on the role of TET proteins in regulatory T cells and mechanistic regulation of regulatory T cell stability.
I am a bioengineering Ph.D. student at the University of California, San Diego. I work in Anjana Rao’s lab at the La Jolla Institute for Allergy and Immunology.
Engineer the immune system to better fight disease. I’m testing ways to prevent CD8 cell exhaustion. CD8 cells can become exhausted if they encounter antigen for prolonged times like in a chronic infection or large tumor. Exhausted CD8 cells cannot effectively kill their targets and preventing CD8 exhaustion will help them survive longer to kill more of their targets.
Use the immune system to develop cellular therapies that fight diseases like cancer, infection, and autoimmunity.