UCSC Research Mentors

IRACDA mentors at UCSC that are involved in stem cell research span four departments in the Baskin School of Engineering and the Division of Physical & Biological 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; and bioinformatics approaches that integrate and display all large-scale data sets collected from 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.

The Carpenter lab focuses on the role of long noncoding RNAs, (lncRNAs) in immune development. There are 16,000 lncRNAs identified in the human genome and the Carpenter lab is interested to discover functionally conserved genes that are critical for controlling macrophage development from hematopoietic stem cells (HSCs) and downstream inflammatory functions. They employ a host of approaches to tackle these questions and to understand lncRNA’s mechanism of action: RNA-seq, high throughput CRISPR-based screening, and they have generated mouse models for in vivo interrogation of function.

The Chen lab studies development of the cerebral cortex in the mammalian brain. Research in the lab focuses 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 embryonic stem cells, mouse genetics, neural anatomy, ChIP-seq and genomics, and electrophysiology to answer these questions.

Dr. Feldheim's goal is to advance the understanding of how retinal ganglion cells (RGC), the neurons that project information from the eye to the brain, develop during embryogenesis from embryonic stem cells, 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, and the behavioral consequences to the animal when they are disrupted. His laboratory's 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.

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. They have discovered that during pregnancy the prodigious cell growth required to build a milk supply results in DNA damage, triggering endoreplication and the creation of binucleated, milk-producing alveolar cells (AVs). This research addresses the public health concern of lactation insufficiency—a significant challenge for women’s and children’s health worldwide. Studies show that mother’s milk is optimal nutrition, and the use of breast milk substitutes increases the risk of morbidity and mortality among infants.

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. Indeed, there is mounting evidence from worms to mammals, including humans, that parental environment can influence phenotypes in future generations. 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 ad-dress these questions, Dr. Sharma uses a unique and powerful combination of molecular, genetic, reproductive, and genomic approaches in the mouse.

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.

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 Drosophila 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. 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 Vaske lab hopes to help resolve diagnostic odysseys for families affected by developmental disorders. Individual genetic disorders, although rare, collectively comprise over 15,500 conditions affecting about 13 million Americans. One category, developmental disorders, often result in early mortality or lifelong impairment. Early diagnosis is critical to enhancing patient outcomes. Current approaches used in medical genetics fail to achieve a diagnosis in the majority of patients, especially in cases of developmental disorders with complex phenotypes. The Vaske lab is developing novel genomic approaches, such as the analysis of germline RNA and long-read sequencing that are designed to identify novel molecular aberrations that could be linked to the pathogenesis of human developmental genetic disorders. These identified molecular aberrations can be studied in the laboratory using molecular and cellular 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, or-ganoid culture, CRISPR genome-editing, and single cell RNA-seq.

Dr. Forsberg's mission is to determine how hematopoietic stem cells (HSCs) achieve homeostasis in blood and immune systems throughout life. Using mouse models, 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. The lab's recent discovery of a developmentally restricted HSC that has unique self-renewal and differentiation properties has sparked intense interest in the regulation of HSC lineage potential at different developmental stages. 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.

The Haussler lab combines mathematics, computer science, pluripotent stem cells 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. Haussler also leads the Braingeneers project aimed at developing scalable and robust methods for long-term experimentation on cerebral cortex organoids aimed at understanding how recent genomic evolution affects human brain development, function and susceptibility to neurodevelopmental diseases like autism.

Dr. Kim focuses on determining the molecular mechanism by which RAS signaling regulates the noncoding transcriptome during human embryonic development. Dr. Kim’s lab uses genomic, single cell, and genome engineering approaches to uncover the functions of RAS-regulated noncoding RNAs in human pluripotent stem cells. In particular, they investigate the potential roles of those RNAs that are released in extracellular vesicles in the pluripotent state. Understanding of how this fundamental signaling pathway regulates the noncoding transcriptome will provide novel insights into pluripotent stem cell biology.

One of Dr. Salama's major goals is to understand how co-evolution of retrotransposon elements (RTEs) and KRAB zinc finger proteins (KZNFs) have resulted in new gene regulatory modules and how these modules con-tribute to human embryonic development and pluripotency. Methods developed in the lab will reveal the roles that evolutionary changes to both KZNFs, as well as the role their RTE/host targets play in controlling transcription in pluripotent stem cells and in early embryonic cell types. In a second project to understand developmental neurogenesis and the regulation of neural progenitor cells by NOTCH signaling, Salama will test the hypothesis that NOTCH2NL genes are required for normal human brain development and that alterations in their gene dosage contribute to the neurological phenotypes observed in patients with 1q21.1 distal deletions and duplications, which include congenital anomalies, autism, schizophrenia, and learning deficits/intellectual disability.

Dr. Shariati’s lab uses pluripotent stem cells to gain insight into the early stages of human embryonic development. A common cause of early preimplantation failure in embryonic development are errors in segregation and replication of genomic content during the first few mitoses. A major goal of the Shariati lab is to gain mechanistic insight into early embryonic genomic instability using stem cell-based models of pre-implantation development. The Shariati lab combines the power of emerging technologies such as single cell quantitative microscopy, single cell genomics and CRISPR genome editing to identify molecular origin of early failure of embryonic development.

Dr. Partch is interested in the intersection between stem cells and circadian rhythms. Several years ago, her lab discovered a cancer-testis antigen, PASD1, whose expression is normally restricted to germline sper-matagonial stem cells (SSCs), but becomes upregulated in a variety of somatic tissues in cancer. Circadian rhythms place daily limits on cellular proliferation, and as a consequence, circadian clocks are absent from highly proliferative SSCs and are also suppressed or lost altogether in many forms of cancer. Partch's lab recently published that PASD1 works to directly suppress clock function in cancer cells. They are now working to understand the basis by which this stem cell-specific factor suppresses the clock and regulates proliferation in cancer and stem cell populations.

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 are generated through structural biology approaches and tested with genetic manipulation and analysis of human embryonic stem cells.

The Chamorro-Garcia lab focuses on understanding how environmental toxicants lead to transgenerational metabolic disruption. Using mice, they study epigenetic mechanisms of inheritance in germline and tissue stem cells. They showed that perinatal exposure to environmental pollutants alters higher order chromatin organization, with subsequent alterations in chromatin accessibility and transcription. Because the changes were found in both somatic and germ cells, they hypothesize that these toxicants act prior to the first cell fate decisions during early embryogenesis.

Contact

Institute for the Biology of Stem Cells (IBSC)

1156 High Street/ Biomedical Sciences, room 444

Santa Cruz, CA 95064

University of California, Santa Cruz

ibsc@ucsc.edu