History
Since it was established in October 1991, the Han lab has developed and engaged in dynamic research programs in the field of cell and developmental biology, with an emphasis on addressing important questions in relatively unexplored areas so that the findings have the potential to be seminal and paradigm shifting. The lab encourages postdocs and students to follow their own ideas during their research, as a number of them have done quite successfully.
Major Contributions to Science by Han lab researchers (since 1991):
Both as a graduate student and postdoctoral fellow, Professor Min Han made landmark discoveries in two different biofrontiers of the time: epigenetics and developmental genetics. In each case, his own creative thinking was inspired by the exploratory mindset of his advisors and the intellectual freedom they granted him. Since starting his own lab in 1991, he has followed a philosophy that model organisms should be used to address outstanding and underexplored biological problems in order to identify new paradigms in relevant fields. Indeed, the Han lab has made numerous risky shifts in research focus between distinct research fields. We have also been bold in using approaches across different disciplines and multiple model systems.
The students and postdoctoral fellows in the Han lab are highly encouraged to follow their own independent thinking and interests to maximize their potential to carry out innovative research. This has proven to be an exceedingly effective approach to train future scientists. Despite running a modest-sized lab in Colorado, 27 former trainees have gone on to become professors/PIs at academic institutions. Dr. Han has discussed this practice in a review article (Han 2015 Sci China Life Sci).
1. Discovered and analyzed the roles of 12+ regulators of the highly-conserved RTK-RAS-MPK signaling pathway
When the Han lab was established in 1991, developmental genetics in worms and flies demonstrated the tremendous power to reveal the functions and mechanistic detail of major signal transduction pathways. The Han lab has employed several genetic suppressor screens to identify >12 factors downstream of Ras in the conserved RTK/Ras pathway, which controls developmental fate specification and cell proliferation in multicellular organisms. Our work, represented by a long list of papers, has made important contributions to the relevant fields. Several mammalian genes in the pathway, such as KSR, SUR-8 and SUR-2/MED23, bear the names from our studies in C. elegans. We also pioneered the chemical/genetic analysis in C. elegans by testing the effects of two ras inhibitors in 1995.
2. Established the concept of universal pairing of the SUN-KASH proteins at the nuclear envelope, and pioneered the study of their functions in multiple cellular/developmental events in both C. elegans and mice.
Through genetic and molecular analysis of three genes involved in nuclear migration and anchorage, we made breakthrough findings regarding nuclear envelope proteins that mediate nucleus-related cellular functions. The Malone et al. 1999 paper (Dev) defined the SUN gene family after cloning the unc-84 gene and identifying mammalian SUN1 family proteins. The next two papers (Starr et al. 2021 Dev; Starr and Han 2022 Science) defined the KASH domain and proposed the concept of the “universal” KASH-SUN pairing at the NE (LINC complexes). These published findings ignited a wave of studies on these proteins that have now become a popular research area. We also pioneered the mouse genetic analysis to understand the physiological roles of the SUN-KASH complexes in muscle development, neuronal migration, gametogenesis, and DNA damage responses (9 high impact papers). Six researchers who worked on these proteins have become professors/PIs.
3. Discovered the essential role of GW182 family proteins in miRISCs and developed biochemical and genetic methods to systematically analyze the in vivo miRNA-target interactions for different physiological functions
Ding et al. 2005 (Mol Cell) was the first paper to show that a GW182 family protein is required for miRNA functions, binds to AGO and miRNAs, and brings miRISCs to P-bodies. We then pioneered the CLIP biochemical approach to systematically identify and analyze the miRNA-target interaction network under true physiological conditions, including at different developmental stages and in specific tissues (Zhang et al, 2007 Mol Cell; 2009 Dev; Kudlow et al., 2012, Mol Cell; Than et al., 2013, Plos Genetics). Adding combinatorial genetic tools, we have effectively uncovered important roles of many non-essential miRNAs in stress response and development.
4. Discovered unknown roles of tumor suppressors and apoptotic caspases masked by “genetic redundancy”
Genetic redundancy associated with structurally unrelated genes is a common phenomenon and an impediment to the functional dissection of a genome. Over the years, my lab has tackled this problem by doing combinational genetics. The most innovative studies used two systematic approaches to identify many “hidden” functions and “redundant” genes associated with Rb and Pten (Fay et al. 2002 Genes Dev; Suzuki and Han 2006, Genes Dev). Cui et al. 2006 (Dev Cell) also made a breakthrough discovery by showing that the SynMuvA and SynMuvB genes (including Rb) redundantly repress transcription of lin-3/EGF in the epidermis to prevent inappropriate cell signaling, indicating de-repression of growth factors as an important role of tumor suppressors. We later uncovered the role of Rb in regulating starvation-induced stress responses.
More recently, a “synthetic phenotype” screen led to the seminal finding of non-apoptotic and non-canonical functions of an apoptotic caspase in regulating gene expression dynamics (Weaver et al., 2013, eLife). We then uncovered an underlying mechanism and roles of caspase in stress responses (Weaver et al., 2017, Dev Cell; Weaver et al. 2020, Dev Cell)
5. Uncovered multiple novel mechanisms by which animals sense the level of specific fatty acids and nucleotides to regulate animal development and behaviors
In the early 2000s, propelled by our prior analysis of human macular degeneration, which revealed a role for a fatty acid (FA) elongase, we made a bold move into the wide-open field of lipid functional analysis. In the early years, we focused our efforts on understanding how specific FA variants critically influence specific cell signaling events and cellular functions. FAs are structurally diverse (>100 variants), and their levels are strictly maintained. Yet, little is known about the functional consequences of these variations, nor how animals achieve proper lipid composition in their membranes during development. The 2004 Kniazeva et al. paper (PLoS Biol) describes the striking, essential functions associated with the obscure but conserved monomethyl branched-chain fatty acids (mmBCFAs) (Faculty of 1000 Exceptional). Our 2012 paper described a highly innovative study showing how animals use FA variants to alter phospholipid composition at a specific stage (early embryo), which in turn specifically affects a signaling event (IP3 signaling) for membrane dynamics. We combined complex genetics with lipid mass spectrometry and biochemistry in this extremely satisfying study (Kniazeva, Shen and Han 2012 Genes Dev).
We then aimed to uncover mechanisms that sense the level of FA and nucleotide variants to regulate development, reproductivity, and behaviors, and discovered four such novel systems, reported in a series of high impact papers. (1) A TORC1-mediated intestinal system to sense the level of mmBCFA and GlcCer (Zhu et al. 2013 eLife; Kniazeva et al. 2015 Dev Cell; Zhe et al. 2015 Genes Dev;Jia et al. 2019 ;Sewell et al. 2022 iScience) which has now been shown to sense the overall amino acid level for postembryonic development (work by former postdoc Huanhu Zhu). (2) A Notch Receptor pathway that senses the level of pyrimidine to regulate germ stem cell proliferation (Chi et al. 2016 Genes Dev;Jia et al. 2020 Cell Rep). (3) An intestinal ATP-sensing pathway that perceives the change of vitamin B2 level to regulate protease expression and food behaviors (Qi et al. 2017 eLife). (4) Acyl-CoA synthase 4 (ACS-4)–regulated myristoylation that senses the level of myristic acid to regulate sex-determination activity and the onset of oogenesis (Tang and Han 2017 Cell), which may present a mechanism underlying a longstanding theory that fat level dictates the reproductive decision in females (reproductive adaptation). The finding of how nutrients (FAs) act as environmental factors to regulate sex determination also has significant implications on the non-karyotype influence of sex determination. Moreover, we revealed the role of myristoylation in fat deprivation-induced muscle degradation (Tang et al. 2021 Cell Rep).
6. Made paradigm-shifting discoveries of unexpected beneficial roles of two microbial molecules on the physiology of host animals
Employing innovative genetic screens, we identified beneficial roles of two microbial metabolites on host physiology. First, we discovered a surprising role of the siderophore enterobactin (Ent) in promoting iron uptake and development in host animals (Qi and Han, Cell 2018; Sewell et al. under review). Mechanistically, we showed that Ent-mediated iron uptake into the host mitochondria is facilitated by Ent interaction with the ATP synthase α-subunit, which points to a novel mechanism for iron transport into mitochondria. Further studies in mammalian cells and mice suggest that such a mechanism is conserved in mammals, and Ent may potentially be used as a new treatment for iron deficiency anemia. Second, we also uncovered a prominent role of bacterial cell wall derivatives, peptidoglycan (PG) muropeptides, in promoting mitochondrial homeostasis and animal development (Tian and Han, Dev Cell 2022). Interestingly, PG muropeptides execute this role at least in part by binding and promoting the activity of ATP synthase, which points to the likely first agonist of ATP synthase. Such a novel role is also conserved in mammals (Tian et al., 2024, Cell Rep).