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 long-term research focus has been to understand how signaling pathways control gene expression, using T cells and other cells of the immune system as models. In collaboration with the lab of Professor Patrick Hogan, we previously showed that gene expression 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 [https://pubmed.ncbi.nlm.nih.gov/12975316/]. 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 programs of T cell “activation” and negative programs, known variously as “exhaustion”, “anergy” or “dysfunction”, that attenuate T cell activation [https://pubmed.ncbi.nlm.nih.gov/25680272/]. These terms all refer to a hyporesponsive state observed under conditions of sustained antigen stimulation in cancer and chronic viral infections.
To understand the biological implications of this hyporesponsive program, our lab uses mouse models of anti-tumor responses that involve adoptive transfer of T cells bearing chimeric antigen receptors (CAR-T cells). Using these models, we have identified important targets of NFAT in the exhaustion program, including transcription factors of the NR4A and TOX families [https://pubmed.ncbi.nlm.nih.gov/30814732/, https://pubmed.ncbi.nlm.nih.gov/31152140/]. Our current research will contribute to a broad mechanistic understanding of the transcriptional mechanisms operating in tumor-infiltrating immune cells, and may spark improved immunotherapies for cancer patients.
More recently, our laboratory has focused on the role of epigenetic regulators in gene expression. In 2009, our laboratory described the enzymatic activities of the three mammalian TET (Ten-Eleven-Translocation) proteins, TET1, TET2 and TET3 [https://pubmed.ncbi.nlm.nih.gov/19372391/]. TET proteins are dioxygenases that oxidize 5-methylcytosine (5mc) to 5-hydroxymethylcytosine (5hmC) and further oxidized products (5fC, 5caC). TET proteins regulate gene expression and enhancer activity, and play a central role in cell lineage specification, embryonic development, neuronal function and cancer [https://pubmed.ncbi.nlm.nih.gov/31965999/]. There is a notable association between TET loss of function and cancer. TET2 loss-of-function mutations are frequently observed in myeloid and lymphoid malignancies, but many other cancers – solid cancers as well as cancers of the blood – can be identified by the fact that they display low 5hmC levels even in the absence of any mutations in TET2 or the other TET genes [https://pubmed.ncbi.nlm.nih.gov/21057493/]. Indeed, diverse metabolic aberrations, found in many solid cancers, lead to profound losses of TET function and likely contribute to oncogenesis [https://pubmed.ncbi.nlm.nih.gov/25132561/, https://pubmed.ncbi.nlm.nih.gov/26595486/, https://pubmed.ncbi.nlm.nih.gov/31467060/].
Using inducible mouse models developed by our laboratory, we have shown that deletion of two or more TET proteins leads to aggressive blood malignancies, characterized by increased levels of DNA damage [https://pubmed.ncbi.nlm.nih.gov/26607761/]. Our current efforts aim to understand the role of TET proteins in maintaining genome integrity. TET loss-of-function is associated with increased DNA methylation, hence the tumor suppressive role of TET proteins has been assumed to involve their ability to maintain DNA in a demethylated state. However, our more recent work has shown that loss of TET proteins also results in a paradoxical loss of DNA methylation in heterochromatin, due at least in part to genome-wide relocalisation of DNA methyltransferases [https://pubmed.ncbi.nlm.nih.gov/31371502/]. Widespread losses of DNA methylation in heterochromatin are also observed in aged and senescent cells. We are currently using models of cancer as well as aging and senescence to investigate the relation between decreased DNA methylation in heterochromatin, reactivation of transposable elements, and DNA damage.
From The Lab
La Jolla Institute receives $ 4.5 mill Cancer Moonshot award
The molecular underpinnings of T cell exhaustion
Exhausted T cells
Dual loss of TET proteins prompts lethal upsurge in inflammatory T cells in a mouse model of lymphoid cancer
Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells
HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells
TET methylcytosine oxidases: new insights from a decade of research
Defining 'T cell exhaustion'
Unusual activity of a Chlamydomonas TET/JBP family enzyme
Dysregulation of the TET family of epigenetic regulators in hematopoietic malignancies
Paradoxical association of TET loss of function with genome-wide DNA hypomethylation
Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition
TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion
Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor
DNA translocation through hybrid bilayer nanopores
Loss of TET2 and TET3 in regulatory T cells unleashes effector function
TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer
NR4A transcription factors limit CAR T cell function in solid tumours
TET Enzymes and 5hmC in adaptive and innate immune systems
Impact of genetic polymorphisms on human immune cell gene expression
YAP and MRTF-A, transcriptional co-activators of RhoA-mediated gene expression, are critical for glioblastoma tumorigenicity
Single cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal
TCR signal strength controls thymic differentiation of iNKT cell subsets
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
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
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
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2
NFAT, immunity and cancer: a transcription factor comes of age
The transcriptional control of the perforin locus
Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis
Pore architecture of the ORAI1 store-operated calcium channel
Molecular basis of calcium signalling in lymphocytes: STIM and ORAI
A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo
Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells
The effect of 5-hydroxymethylcytosine on bisulfite sequencing
STIM1 gates the store-operated calcium channel ORAI1 in vitro
Juan Carlos Castelan Angel
Edahi Gonzalez Avalos
I graduated from the National Autonomous University of Mexico in 2016 with a Bachelor in Genomic Sciences. While and after obtaining my degree I was working as a bioinformatician at the LJI in the Signaling and Gene expression group, headed by Dr. Anjana Rao and Dr. Patrick Hogan. After my degree completion I got accepted to the Boinformatics and Systems Biology Graduate Program at University of California, San Diego (UCSD), where I am currently a 2nd year student being my mentor and co-mentor Dr. Anjana Rao and Dr. Ferhat Ay respectively.
Besides aiding in several genomic analysis of sequencing data, my main focus is the study of the effect of TET proteins (particularly 5-hydroxymethylcytosine, 5hmC) in genomic interactions compared to H3K27 modifications as well as other epigenetic marks.
Daniela Samaniego Castruita
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 Immunology.
Joyce is working to elucidate the roles of these transcription factors in CD8 T cell exhaustion.
Research Tech I
Postdoc Fellow (3 years)
Research Tech 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 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 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.
Lab Manager/Research Technician IV
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 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.
Hyungseok Seo received a B.S. degree in Animal Biotechnology from Seoul National University (Seoul, Korea) in August, 2012, after which Hyungseok Seo started my graduate study in immunology at Seoul National University (Seoul, Korea) under the guidance of Dr. Chang-Yuil Kang and received my PhD degree in August, 2017. Currently, he is postdoc researcher in Dr. Anjana Rao’s laboratory at the La Jolla Institute for Immunology.
Dr. Hyungseok Seo’s postdoctoral research focus on elucidating the mechanisms underlying immune cell exhaustion by epigenetic reprogramming under the guidance of Dr. Anjana Rao. Dr. Hyungseok expect that his studies will provide new insight into the transcriptional and epigenetic regulation of tumor-infiltrating innate immune cells as well as provide clues to develop tumor immunotherapies that target exhausted CD8 T cells and NK cells in advanced cancer patients.
Vipul Shukla, Ph.D.
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 Immunology.
Vipul’s research focus is on investigating the role of TET proteins as regulators of genomic stability.
Rotating Graduate Student
Postdoc Fellow (0 year)
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 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 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.