Han JD (2012) Birth Defects Res C Embryo Today "An aging program at the systems level?"

Han JD

[Birth Defects Res C Embryo Today, 2012]

Many genes and pathways are known to modulate lifespan in various organisms, but it remains unclear whether there exists a common aging program, and how individual variations of lifespan can occur in an isogenic population. Recent studies on aging regulation at the systems and epigenetic levels point to the possibility of regulating and potentially reversing the aging epigenome and transcriptome, resulting in differential aging status and aging rate in different individuals. Here, the author summarize some of these findings and discuss the possibility of integrating multiple layers of aging regulation at the systems level, to identify an aging program that can explain lifespan variations introduced by environmental and developmental history.

Han H-P et al. (1992) Worm Breeder's Gazette "Expression and Localization of the cha-1 and unc-17 Gene Products"

Rand JB, Duerr JS, Han H-P

[Worm Breeder's Gazette, 1992]

EXPRESSION AND LOCALIZATION OF THE cha-l AND unc-17 GENE PRODUCTS He-ping Han, Janet Duerr, and Jim Rand, Oklahoma Medlcal Research Foundation, Oklahoma Clty, OK 73104

Chen W et al. (2015) Oncotarget "Aging phenomics enabled by quantitative imaging analysis."

Han JD, Chen W

[Oncotarget, 2015]

Gruber J et al. (2017) Cell "Microbiome and Longevity: Gut Microbes Send Signals to Host Mitochondria."

Kennedy BK, Gruber J

[Cell, 2017]

The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han etal. use the workhorse of aging research, C.elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first steptoward analogous manipulations to modulate human aging.

Visentin C et al. (2017) Hum Mol Genet "Epigallocatechin-3-gallate and related phenol compounds redirect the amyloidogenic aggregation pathway of ataxin-3 towards non-toxic aggregates and prevent toxicity in neural cells and Caenorhabditis elegans animal model."

Relini A, Tortora P, Gatta E, De Gioia L, Airoldi C, Natalello A, Vertemara J, Visentin C, Penco A, Pellistri F, Regonesi ME, Bonanomi M

[Hum Mol Genet, 2017]

The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e., (-)-epigallocatechin gallate (EGC), and gallic acid (GA). We analyzed the aggregation pattern of ATX3-Q55 and of the N-terminal globular Josephin domain (JD) by assessing the time course of the soluble protein, as well its structural features by FTIR and AFM, in the presence and the absence of the mentioned compounds. All of them redirected the aggregation pattern towards soluble, SDS-resistant aggregates. They also prevented the appearance of ordered side-chain hydrogen bonding in ATX3-Q55, which is the hallmark of polyQ-related amyloids. Molecular docking analyses on the JD highlighted three interacting regions, including the central, aggregation-prone one. All three compounds bound to each of them, although with different patterns. This might account for their capability to prevent amyloidogenesis. Saturation transfer difference NMR experiments also confirmed EGCG and EGC binding to monomeric JD. ATX3-Q55 pre-incubation with any of the three compound prevented its calcium-influx-mediated cytotoxicity towards neural cells. Finally, all the phenols significantly reduced toxicity in a transgenic Caenorhabditis elegans strain expressing an expanded ATX3. Overall, our results show that the three polyphenols act in a substantially similar manner. GA, however, might be more suitable for antiamyloid treatments due to its simpler structure and higher chemical stability.

Greenwald IS et al. (1990) Cell "Cell fates in C. elegans: in medias ras."

Greenwald IS, Broach JR

[Cell, 1990]

ras proteins play a central role in controlling cell proliferation in a variety of organisms and also appear to mediate specific developmental processes in certain cells. Nonetheless, how ras protein activity is regulated and how ras protein activation yields its biological effect have not been clearly defined in any metazoan. Now, Han and Sternberg (1990a) have found that a ras protein is encoded by the C. elegans let-60 gene. Since powerful classical and molecular genetic methods are available for C. elegans, this finding offers great promise for identifying components of the ras pathway and defining the nature of their interactions in this organism. In addition, the extensive literature on the biochemistry and genetics of ras function in other organisms should greatly facilitate translating genetic analysis of let-60 (Beitel et al., 1990; Han and Sternberg, 1990b) into detailed molecular models of cell fate determination.

Chen W et al. (2016) Methods "Bioimaging for quantitative phenotype analysis."

Han JD, Chen W, Xia X, Chen X, Huang Y

[Methods, 2016]

With the development of bio-imaging techniques, an increasing number of studies apply these techniques to generate a myriad of image data. Its applications range from quantification of cellular, tissue, organismal and behavioral phenotypes of model organisms, to human facial phenotypes. The bio-imaging approaches to automatically detect, quantify, and profile phenotypic changes related to specific biological questions open new doors to studying phenotype-genotype associations and to precisely evaluating molecular changes associated with quantitative phenotypes. Here, we review major applications of bioimage-based quantitative phenotype analysis. Specifically, we describe the biological questions and experimental needs addressable by these analyses, computational techniques and tools that are available in these contexts, and the new perspectives on phenotype-genotype association uncovered by such analyses.

Yeh Chan-Hsien et al. (2007) International Worm Meeting "Screen for TLK-1-interacting proteins."

Yi-Chun Wu, Yeh Chan-Hsien, I-Ju Lee

[International Worm Meeting, 2007]

Tousled-like kinases (TLKs) form a conserved serine/threonine kinase family in multi-cellular organisms and have been implicated in transcription, DNA replication and repair and chromosome assembly and segregation. The tlk-1(RNAi) mutants exhibited defects in chromosome condensation and segregation. Previous studies of C. elegans TLK-1 indicates that tlk-1 may act in chromosome assembly by phosphorylating Asf-1 (anti-silencing function protein) and contribute to chromosome segregation as a substrate and activator of the Aurora B kinase AIR-2 (Han et al, 2005). To identify more TLK-1-interacting proteins, we performed a yeast-two hybrid screen. In the screen we isolated DLC-1 (Dynein light chain). DLC-1 is localized to spindle fiber during mitosis and this localization pattern is disrupted in tlk-1(RNAi) embryos. We are currently performing experiments to verify the interaction between DLC-1 and TLK-1 in vivo and investigating if TLK-1 may phosphorylate DLC-1. Reference Han, Z., Riefler, G.M., Saam, J.R., Mango, S.E., and Schumacher, J.M. (2005) Curr. Biol., 15, 894-904.

Dent JA et al. (1998) Mech Dev "Post-embryonic expression pattern of C. elegans let-60 ras reporter constructs."

Dent JA, Han M

[Mech Dev, 1998]

let-60 ras plays roles in the differentiation of several C. elegans tissues (Yochem, J., Sundaram, M., Han, M., 1997. Ras is required for a limited number of cell fates and not for general proliferation in Caenorhabditis elegans. Mol. Cell. Biol. 17, 2716-2722). To understand the transcriptional regulation of ras and to identify new functions for ras in development, we examined expression patterns of let-60::lacZ and let-60::GFP reporter constructs in C. elegans hermaphrodites. Fusion constructs were expressed in vulval precursor cells, sex myoblasts and in cell lineages of the somatic gonad, germline cells (GFP construct only), hypodermis, muscle and nervous system.

JD Kormish et al. (1999) International C. elegans Meeting "A genetic screen for genes involved in gut development and differentiation"

JD McGhee, JD Kormish

[International C. elegans Meeting, 1999]

To investigate genes potentially involved in gut development and differentiation, we are developing a genetic screen for gut obstructed (gob) mutants. The gut specific elt-2 GATA factor appears necessary for correct gut cell development. elt-2 null mutants arrest as L1s with a blocked intestinal lumen and abnormal brush border (1). When elt-2 null mutants are fed on a mixture of fluorescent beads and Escherichia coli , the beads collect as a large "gob" in the posterior pharynx and anterior gut that can be easily detected under the dissecting microscope. We are now using this gut obstructed phenotype to screen for mutants that should potentially identify genes involved in gut development. Preliminary results of this screen are promising, as several candidates have already been isolated. 1) Fukushige T, Hawkins MG and McGhee JD (1998) Dev Biol 198(2):286-302