UCSC faculty members involved in stem cell research span five departments in the Baskin School of Engineering and the Divisions of Physical & Biological Sciences, Humanities, and Social Sciences.
Their research takes several approaches: studies in key model organisms, such as the mouse, fruit fly, and worm, using genetics and molecular biology; computational approaches for understanding gene regulatory networks, expression patterns, and alternative splicing; bioinformatics approaches that integrate and display all large-scale data sets collected from stem cell research; and examination of the social and ethical issues surrounding stem cell research.
Individual projects focus on a number of biological systems, including germ line and nervous system development, epigenetic mechanisms of gene regulation, blood cell differentiation, mammalian embryonic cell fates, wound healing, and the immune system.
Studying post-transcriptional control of gene expression in a variety of cell types, in particular systems-level regulation mediated by sequestration and competition phenomena.
The Carpenter lab focuses on understanding the complex molecular mechanisms that drive inflammation in the body. Recent evidence shows that a group of RNA molecules known as long noncoding RNAs (lncRNAs) plays important roles in diverse biological functions, including the inflammatory response. They are studying lncRNAs to gain an understanding of their function within cells of the immune system, which could lead to insight into human disease and perhaps novel targets for therapeutic intervention for inflammatory conditions
The Chen lab studies development of the cerebral cortex in the mammalian brain focusing on three related questions. 1) What is the lineage relationship between cortical neural stem cells and different types of cortical excitatory neurons and glial cell types? 2) What mechanisms regulate the lineage progression of neural stem cells? 3) What molecular mechanisms direct the specification of different subtypes of cortical excitatory neurons from multipoint neural stem cells? Dr. Chen uses a combination of approaches, including mouse genetics, neural anatomy, ChIP-seq and genomics, and electrophysiology.
Dr. Feldheim researches how retinal ganglion cells (RGC), the neurons that project information from the eye to the brain, develop during embryogenesis and are maintained in adulthood. He uses a combination of mouse molecular genetics, anatomical tracing, and neural activity recordings to determine the genes that are required for RGC health and function. His research provides insights into mechanisms that determine how visual circuits develop, as well as the mechanisms of neurodegenerative diseases, such as glaucoma, in which RGCs die.
Stem cell function is essential for tissue homeostasis and renewal and their loss may explain the multi-system failure that occurs in aging. Preliminary analysis of a mouse model that lacks telomerase RNA and has short telomeres indicates that telomere shortening leads to loss of stem cells, and organ failure. The Greider lab is currently using mammalian tissue culture cells to study the fundamental mechanisms of telomere length maintenance and consequence of short telomeres to understand stem cell failure.
Dr. Hinck uses the breast as a model system to study how extracellular factors and the niche regulate the balance between stem/progenitor cell expansion, renewal and differentiation. Recently, her lab has focused on determining how alveolar progenitor cells generate the millions of differentiated cells required for every pregnancy and estrus cycle. Elucidating the pathways governing these events is of great interest. This research addresses the public health concern of lactation insufficiency—a significant challenge for women’s and children’s health worldwide. Hinck's studies are defining a targetable pathway to enhance milk production.
The Kim lab focuses on understanding the organizational logic of long-range neural circuits and the molecular mechanisms of their development using the mouse cortex as a model. A major research goal of Dr. Kim is to answer how a population of neural progenitors/stem cells in a single cortical area develops into diverse subtypes each projecting to particular brain areas and receiving specific brain-wide inputs. His lab is examining how genetic programs and neuronal activity interact to construct connectivity.
Post-transcriptional gene regulation governs the fate and function of virtually every human gene product. Dr. Sanford's goal is to determine the underlying molecular basis for RNA-targeted regulatory mechanisms. His laboratory uses stem cells as a model to discover the biological functions and mRNA targets of RNA binding proteins (RBPs). Sanford's research program focuses on understanding how the processes of alternative pre-mRNA splicing and translational control contribute to the gene regulatory programs that drive stem cell differentiation.
Dr. Sharma’s goal is to elucidate the mechanism of intergenerational epigenetic inheritance by examining how environmental conditions modulate specific epigenetic marks in germ cells and how those marks influence development of offspring. The possibility that environment can influence phenotypes in descendants has tremendous implications for basic biology and public health and policy. To elucidate the mechanism of intergenerational epigenetic inheritance, Dr. Sharma's lab examines three key steps: 1) how epigenetic information signals are generated in gametes, 2) how those signals are influenced by environment, and 3) how those signals influence early embryonic gene expression and development. To address these questions, Dr. Sharma uses a unique and powerful combination of molecular, genetic, reproductive, and genomic approaches in the mouse.
Dr. Strome's goal is to understand how epigenetic information is transmitted across generations and during development, including its importance in the normal development of germ cells in the offspring. Epigenetic mechanisms enable gene expression and development to be regulated not only by DNA sequence, but also by how DNA is packaged into chromatin. In C. elegans, a set of histone-modifying enzymes enables the parental chromosomes inherited by embryos to transmit an epigenetic “memory of the germline” from parent germ cells to the primordial germ cells (PGCs) in offspring. Germ cells that do not inherit that memory die. Strome's lab uses this as a powerful model system to study fundamental transgenerational epigenetic mechanisms.
Dr. Sullivan studies the role of endocytic vesicle trafficking in regulating stem cell differentiation and self-renewal. His lab takes advantage of the well-studied neuroblast stem cell model of the Drosophila third instar larva. In addition to being amenable to sophisticated molecular genetic techniques, fixed and live fluorescent analysis can be performed readily in this system. Specifically, Sullivan focuses on the role of Rab11, a key component of the recycling endosome, and its effectors on stem cell self- renewal. Over-expression of Nuf, a conserved Rab11 effector, disrupts stem cell self-renewal. Future studies include investigating the mechanisms underlying endosome segregation in stem cell divisions and the role of endosomal components in mediating stem cell self renewal.
The Sikandar lab leverages single cell transcriptomic data to elucidate functional heterogeneity in normal mammary stem and progenitor cells. Determining lineage hierarchies and differentiation pathways in mammary epithelial cells will allow for novel solutions to global health problems such as lactation insufficiency and poor nutrition in infants. A major focus of the lab is to determine molecular mechanisms regulating vesicle trafficking for exocytosis (e.g. milk secretion during lactation) and endocytosis (e.g. processing of hormonal receptors like estrogen receptor (ER), progesterone receptor (PR) and prolactin receptor (PRLR). Our lab uses functional genomics, lineage tracing, organoid culture, CRISPR genome-editing, advanced 3-D imaging and live cell imaging to identify novel molecular pathways specific to sub-populations of mammary epithelial cells.
Using a combination of genetic, biochemical, and molecular approaches to study chromatin-remodeling complexes, including their roles in transcriptional regulation, structural maintenance, post-translational modifications, and cell fate specification.
Pediatric cancers are disorders of normal development and differentiation. The Vaske lab studies these disorders using a combination of bioinformatic, genomic and molecular biology approaches.
One of Dr. Wang's main goals is to dissect the internal and extrinsic signaling pathways that regulate the stem cell plasticity of prostate basal cells. During prostate organogenesis, epithelial basal cells behave as stem cells to produce luminal cells and neuroendocrine cells. This capacity is preserved, but restricted, in the adult organ, and is only reactivated during prostate epithelium regeneration after luminal layer damage. To understand the stem cell plasticity of basal cells, Wang's lab employs multiple approaches, including genetic lineage tracing, organoid culture, CRISPR genome-editing, and single cell RNA-seq to 1) investigate the signaling pathways that regulate basal-to-luminal differentiation, 2) characterize stromal niche cell types and markers, and 3) identify gene regulatory network within basal cells.
Understanding the role of epithelial cell differentiation in epidermal wound healing and in cutaneous immune responses. Characterizing the development and homeostatic maintenance of regulatory T cells.
Dr. Zuo's lab studies glia-neuron interaction, structural and functional plasticity during development, learning, and pathologies. The lab is particularly interested in the neural circuit change in developmental psychiatric disorders.
Dr. Forsberg's mission is to determine how hematopoietic stem cells (HSCs) achieve homeostasis in blood and immune systems throughout life. Using the mouse as a model, her lab investigates blood cell production and specification of hematopoietic cells in the very early embryo, during adulthood, and in aging. The Forsberg lab dedicates substantial effort towards understanding the epigenetic inheritance of properties in ontogeny and upon differentiation. Important goals are to determine how maternal immune challenges during pregnancy affect the development and function of fetal HSCs and their descendant blood and immune cells, and how exposure to immune insults during perinatal life affects life-long health and susceptibility to disorders later in life.
Dr. Green is the co-director of the UCSC Paleogenomics lab. The lab's research focuses on a wide range of evolutionary and ecological questions, mostly involving the application of genomics techniques to better understand how species and populations evolve through time. Dr. Green's stem-cell related research addresses the genetic underpinnings of human-specific brain evolution and cognition of the human brain. The lab uses genomic methods to insert archaic versions of genes from extinct relatives (Neanderthals and Denisovans) into human-derived cells which will be grown into organoids. In the organoids, the biology of cells that carry genetic variants that have been extinct for thousands of years can be studied to help discover recently evolved functions in human brain development and cognition.
The Haussler lab combines mathematics, computer science, and molecular biology to study human development and evolution. The bioinformatics group develops new statistical and algorithmic methods to explore the molecular function and evolution of the human genome, integrating cross-species comparative and high-throughput genomics data to study gene structure, function, and regulation.
The “wet lab” explores and validates predictions generated from computational genomic research about the evolution and function of human genes. The lab uses embryonic and induced pluripotent stem cells to investigate neurodevelopment and cancer development from a functional and evolutionary perspective. Research project areas include genome evolution, comparative genomics, alternative splicing, and functional genomics.
Dr. Kim focuses on determining the molecular mechanism by which RAS signaling regulates the noncoding transcriptome during human embryonic development. Dr. Kim use genomic, single cell, and genome engineering approaches to decode the functions of RAS-regulated noncoding RNAs in human pluripotent stem cells. His lab also investigates the potential roles of RAS-regulated noncoding RNAs that are released in extracellular vesicles in the pluripotent state. Deepening our understanding of how this fundamental signaling pathway regulates the noncoding transcriptome will provide novel insights into pluripotent stem cell biology.
How stem cells decide to choose between two conflicting fates, division vs. differentiation, is an unsolved mystery of stem cell biology. The overarching goal of the Shariati lab is to determine the mechanisms that link cell division to cellular differentiation in stem cells. The lab combines emerging genome-editing technologies with single cell imaging to determine regulatory principles of cell fate decisions in pluripotent stem cells.
The Stuart lab uses data-driven approaches to identify and characterize genetic networks, investigate how they have evolved, and then use them to simulate and predict cellular behavior. The lab’s approach is to design computational models and algorithms that integrate high-throughput molecular biology datasets (genomic, epigenomic, and functional genomic) to predict cellular- and organism-level phenotypes. Dr. Stuart’s group created the metadata standards by which all data in UCSC Stem Cell Hub (SCHub) was annotated. The standard defined the minimal information about a stem cell experiment (MISCE) and has been used for the length of the project to create coherent descriptions across labs. The Computational Genomics Laboratory assists in core informatics processing of data and in downstream analysis of gene expression and epigenomics to identify cell states and transitions.
Dr. Partch is interested in the intersection between circadian rhythms and cancer stem cell growth. Glioblastoma stem cells (GSCs) depend on the circadian pioneer transcription factor CLOCK:BMAL1 for their continued growth and self-renewal. Recent work has shown that chemical biology approaches resulting in inhibition of CLOCK:BMAL1 potently disrupt GSC growth and improve survival in animal models of glioblastoma. Partch’s lab has studied the structure and function of CLOCK:BMAL1 for the last decade, identifying several classes of molecules that directly regulate its activity. They are beginning to use these inhibitors to develop new therapeutic approaches to treat glioblastoma.
Dr. Rubin is determining and targeting molecular mechanisms controlling stem cell and cancer cell division. His lab studies the structure and function of transcription factor complexes and their regulators that modulate cell-cycle dependent gene expression. They answer how these complexes are assembled, how they are regulated, and how their structural properties mediate their function. Projects include investigating critical oncogenes and tumor suppressors, such as Rb, E2F, Myb, and FoxM1, which play critical roles in stem cell division and renewal. Hypotheses for function and regulation are generated through structural biology approaches and tested with genetic manipulation and analysis of human embryonic stem cells.
The Chamorro-Garcia lab is interested in better understanding mechanisms of genome-environment interactions. Environmental factors such as pollutants, diets, temperature or stress, can contribute to disease not only in individuals directly exposed to the stressor but also in their unexposed descendants. Our work integrates epigenomic, transcriptomic, and physiological analyses to reveal how environmental stressors lead to the modulation of the expression of the genome. Our current emphasis is on alterations of chromatin organization during early embryonic development, and on how this disruption is propagated through development and across generations contributing to phenotypic variation and disease.
Dr. Teodorescu is part of three large research projects: Braingeneers, Bioelectronics, and DANSER lab. His stem-cell related work is with the Braingeneers group which employs comparative genomics and primate brain development to model neural activity. The Braingeneers lab is experimenting with cerebral organoids — three-dimensional structures that are formed by self-organization and differentiation of stem cells and function like the brain of a developing embryo.