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Functional Analysis of Metabolic Events, Cell Signaling, and Gene Expression During Animal Development and Stress Response

Research Summary

Min Han uses Caenorhabditis elegans and mouse models to study problems related to animal development, stress response, and human disease, applying both genetic and biochemical methods. The current major focus of his lab is the functional impact of lipid variants and metabolic events, as well as roles of noncoding RNAs.

Since it was established in October 1991, our lab has developed and engaged in dynamic research programs in the field of cell and developmental biology, with an emphasis on important questions in relatively unexplored areas so that the findings have the potential to be seminal and paradigm shifting.

In the early years, we focused on using vulval differentiation as the system to identify and analyze key regulators of the ultraconserved RTK-RAS-ERK signaling pathway. We extended the study to tackle the problem of genetic redundancy of structurally unrelated genes (many encoding tumor suppressors and transcription factors) involved in regulating developmental events. Since the late 1990s, several researchers in our lab have shifted to study the mechanism of cellular and morphogenic events downstream of signaling activities. One such effort led to the discovery of the SUN domain protein family and the universal pairing of the SUN and KASH domain proteins at the nuclear envelope, which triggered a series of studies of the physiological functions of the complexes in multiple developmental events in Caenorhabditis elegans and mice. Another effort led to the discovery of the role of GW182 family proteins in miRNA-mediated gene silencing.

In the 2000s, motivated by a set of studies on human eye diseases, we recognized that the functional specificity of fatty acid and lipid variants is a wide-open area and that the connection between lipid metabolism and development had not yet been extensively studied. Projects in this area have become a major focus of our current lab.

Decoding the Relationship Between Fatty Acid or Lipid Structures and Functions
Fatty acids (FAs) are highly variable in their structures, and these variations greatly contribute to the vast diversity in lipid structures. Despite sporadic reports linking FA variants with human diseases and animal development, their functional specificities have been poorly studied in general. We know little about the mechanism by which these variants contribute to the lipid composition in specific tissues for cellular events under physiological conditions.

Combining genetics with biochemistry, including mass spectrometry, we uncovered spectacular impacts of monomethyl branched-chain fatty acids (mmBCFAs) on cell signaling and development. In one specific example, we showed that acyl-CoA synthetase (ACS) family enzymes critically regulate the incorporation of mmBCFAs into specific phospholipids in the somatic gonad so that proper phospholipid composition is achieved in the zygote. Imbalance of mmBCFA-containing phospholipids compromises IP3 signaling, leading to dramatic disruption of membrane dynamics. Understanding how different FAs are channeled into different high-order lipids and how the lipid composition impacts animal growth and development are two of the focuses of our lab.

Role of an mmBCFA/GlcCer/TORC1 Pathway in Promoting Postembryonic Growth and Development
Regulation of animal development in response to nutritional cues is an intensely studied problem related to disease and aging. The roles of FAs and lipids in target of rapamycin (TOR)-mediated nutrient/food responses are not clear. We found that worms halt postembryonic growth and development shortly after hatching in response to mmBCFA deficiency. We then discovered that an mmBCFA-derived sphingolipid, d17iso-glucosylceramide, is a critical metabolite in regulating growth and development. Further analysis indicated that this lipid function is mediated by TORC1 and antagonized by the NPRL-2/3 complex in the intestine. We also show that this lipid-TORC1 pathway is independent of an insulin receptor (IIS) and transforming growth factor-β (TGFβ) signaling pathways known to regulate postembryonic development in response to nutrient/food availability. These features may suggest that the mmBCFA/d17iso-GlcCer/TORC1 signaling pathway coordinates nutrient and metabolic status with growth and development under specific physiological conditions, advancing our understanding of the physiological roles of mmBCFAs, ceramides, and TOR.

Starvation-Induced Stress Response
How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer. Newly hatched C. elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model to study starvation response. Through a genetic search, we have discovered many factors, including tumor-suppressor Rb and ceramide, that critically promote survival during L1 diapause and likely do so by regulating the expression of genes in both insulin–IGF-1 signaling (IIS)-dependent and -independent pathways.

Global gene expression analyses suggested that Rb maintains the starvation-induced transcriptome and represses the refeeding-induced transcriptome, including the repression of many pathogen/toxin/oxidative stress-inducible and metabolic genes, as well as the activation of mitochondrial respiratory chain genes. The majority of genes dysregulated in starved L1 Rb animals were not found to be dysregulated in fed conditions. Our studies suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment.

The Role of miRNA in Maintaining Gene Expression Dynamics under Various Physiological Conditions
Our interest in miRNA came from the discovery in 2005 of the critical roles of GW182 family proteins (AIN-1 and AIN-2 in C. elegans) in miRNA-mediated gene silencing. Recognizing the limitation of computational methods to identify miRNA targets under true physiological conditions, we developed the novel AIN-1/2–immunoprecipitation (AIN-IP) method to systematically identify miRNA-mRNA interactions. This method is validated by the observation that the enrichment of well-known target mRNAs in the AIN-IP correlates tightly with the levels of corresponding miRNAs and inversely with their cellular protein levels, as well as by bioinformatics analysis by the Victor Ambros lab (University of Massachusetts).

We recognized that the vast majority of miRNA physiological functions are collective effects of miRNA-target interaction networks, and traditional genetic analysis is limited in analyzing these roles. Emphasizing systematic analysis under specific physiological conditions, we examined miRNA-induced silencing complexes (miRISCs) at five different developmental stages and showed that miRNAs preferentially target genes involved in signaling processes and orchestrate temporal developmental programs by coordinately targeting genes involved in particular biological functions.

By analyzing miRISCs in specific tissues such as the intestine, muscle, and neurons, we identified important roles of miRNA regulations in these tissues. For example, intestine-specific AIN-IP analysis led to the discovery that a large number of miRNA-target interactions are devoted to attenuating pathogen/toxin response. In contrast, major miRNA activities in the intestine promote survival from starvation stress by repressing many genes, including those in the IIS pathway. The same miRNAs also act to reestablish developmental programs in animals recovering from the starvation-induced developmental arrest.

We also hypothesized that when miRNA regulation is compromised, a broad range of cellular and developmental processes become vulnerable. We have carried out a large-scale genetic screen to identify roles of miRNAs and other regulatory functions that would otherwise be masked by genetic redundancy.

Human Disease–Related Problems
Using mouse genetics, several graduate students (in collaboration with researchers at Fudan University) have made seminal findings about the physiological functions of the KASH-SUN nuclear envelope complexes that were initially established by our C. elegans studies. They discovered that inner nuclear envelope proteins SUN1 and SUN2 form complexes with outer nuclear envelope proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 for myonuclear anchorage (both synaptic and nonsynaptic) and nuclear movement during neuronal migration and neurogenesis, both in brain and retina. SUN proteins were also found to play critical roles in the anchorage of telomeres to the nuclear envelope for meiotic chromosomal pairing, as well as roles in DNA damage responses in mitotic cells. In addition, by screening a collection of mouse insertion mutants, the lab has identified and analyzed several novel genes involved in obesity-related cellular processes.

A grant from the National Institutes of Health provided partial support for these projects.

As of February 25, 2016

Scientist Profile

University of Colorado Boulder
Molecular Biology