Lizhen Chen, PhD
Lanzhou, Gansu , P.R. China
|2008||PhD||Genetics||University of Georgia
Athens , GA
The goal of our research is to discover molecular pathways involved in aging and diseases, and to translate such findings into potential therapeutic targets. Specifically, our research focuses on genetic and epigenetic regulation of neuronal aging, age-dependent axon regeneration and cancer. We use C. elegans, mouse and cell culture models in our research. We are also collaborating with translational and clinical investigators.
Genetic and epigenetic regulation in axon regeneration
In the mature mammalian CNS, axons regenerate poorly after injury, accounting for permanent functional deficits. In contrary, embryonic and early postnatal animals show a remarkable ability to regenerate axons. Characterization of the mechanisms underlying this inability to regrow is of great interest to human health. It has been shown that injured mature CNS axons can regrow into sciatic nerve grafts transplanted into the lesion site, prompting the notion that successful axon regeneration requires a permissive environment. Research in recent years has also supported the emerging recognition that the intrinsic growth ability of adult neurons is as important as the extrinsic inhibitory factors. We are combining genetic screen and genomic approaches to identify novel regulators, especially intrinsic regulators, which will then be functionally validated.
Microtubule dynamics and aging
Aging impacts the function of the nervous system and is the major risk factor for neurodegenerative diseases and is a fundamental problem in basic neuroscience and in human health. On the other hand, the nervous system corporate the organism’s overall metabolism and affect homeostasis and longevity. Microtubules (MTs) are essential cytoskeleton involved in cell division, shaping the cell and intracellular transport. MT regulation is involved on several levels in neuronal function and maintenance of neuronal structure, and also appears to be a general downstream indicator and effector in age-dependent neurodegeneration. Drugs targeting MT dynamics have been shown to ameliorate the pathogenic symptoms in animal models of neurodegenerative diseases. Mutations in tubulin genes or MT associated proteins have also been reported to affect neuronal integrity during aging. We are interested in understanding the effects of aging on MT organization and testing whether stabilizing neuronal microtubule can delay neuronal aging and promotes longevity.
Role of CELF RNA binding proteins in neuronal development and aging
RNA binding proteins (RBPs) are critical players in gene regulation and are at center stage in our understanding of cellular function in both normal and disease processes. Dysfunction of RBPs and the subsequent disruption of RNA processing are increasingly implicated in neurological disorders including age-associated neurodegneration. CELF RBPs regulate alternative splicing and RNA stability and are expressed in the nervous system. Mutations in CELF genes have been linked to various neuronal disorders, including autism spectrum disorders, schizophrenia and seizures. CELF1 and CEFL2 have been recently identified as a risk factor associated with AD in several independent GWAS analyses. We are interested in the molecular mechanisms by which CELF RBPs regulate neurodevelopment and neurodegeneration.
Enhancer regulation in axon regeneration and cancer
Enhancers are essential distal DNA regulatory elements that control temporal- or spatial-specific gene expression patterns during development and other biological processes. Dysregulation of enhancer function is involved in many diseases including cancer. Enhancer function is regulated by combinations of transcription factors (TFs) and cofactors. Cofactors, including Mediator complex (Mediator), chromatin-remodeling complexes (CRCs), and histone-modifying complexes (HMCs), are recruited to enhancers by pioneer TFs to form combinatorial enhancer complexes. We are investigating the enhancers that are activated or inactivated in response to neuronal injury and during axon regeneration. We are also studying the component changes in enhancer complexes in response to different signals during cancer progression.
|1.||Ko, S. H., Apple, E. C., Liu, Z., & Chen, L. (2020). Age-dependent autophagy induction after injury promotes axon regeneration by limiting NOTCH. Autophagy, 16(11), 2052–2068. https://doi.org/10.1080/15548627.2020.1713645|
|2.||Apple, E., & Chen, L. (2019). Neuronal microtubules impact lifespan. Aging, 11(17), 6616–6617. https://doi.org/10.18632/aging.102224|
|3.||Zhu, C., Li, L., Zhang, Z., Bi, M., Wang, H., Su, W., Hernandez, K., Liu, P., Chen, J., Chen, M., Huang, T. H., Chen, L., & Liu, Z. (2019). A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer. Molecular cell, 75(4), 791–806.e8. https://doi.org/10.1016/j.molcel.2019.06.010|
|4.||Wang, H., Webster, P., Chen, L., & Fisher, A. L. (2019). Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans. Aging, 11(8), 2295–2311. https://doi.org/10.18632/aging.101914|
|5.||Xu A, Zhang Z, Ko S, Fisher L, Liu Z, Chen L (2018). Microtubule regulators regulate neuronal aging and organismal longevity through DAF-16 in C. elegans. Aging Cell. In press.|
|6.||Chen L (2018) Microtubules and axon regeneration in C. elegans. Mol Cell Neurosci. pii: S1044-7431(17)30416-5. doi: 10.1016/j.mcn.2018.03.007.|
|7.||Chen L, Liu Z, Zhou B, Wei C, Zhou Y, Rosenfeld M, Fu X, Chisholm A and Jin Y (2016) CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of syntaxins. eLife.16072. PMID: 27253061|
|8.||Chen L, Chuang M, Koorman T, Boxem M, Chisholm A and Jin Y (2015) Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase. eLife.08695. PMID: 26339988|
|9.||Grill B, Chen L, Bienvenut W, Anderson M, Quadroni M, Jin Y and Garner CC (2012) RAE-1 a novel PHR binding protein is required for axon termination in C. elegans. Journal of Neuroscience 32(8):2628-36 PMID: 22357847|
|10.||Chen L, Wang Z, Hubert T, Ghosh-Roy A, O’ Rourke S, Bowerman B, Wu Z, Jin Y, Chisholm A. (2011) Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron 71(6):1043-57 PMID: 21943602|
|11.||Chen L and Chisholm A. (2011) Axon regeneration mechanisms: insights from C.elegans. Trends in Cell Biology 21(10):577-84 PMID: 21907582|
|12.||Chen L, Zhao P, Wells L, Amemiya C, Condie B, Manley N. (2010) Mouse and zebrafish Hoxa3 orthologs have non-equivalent in vivo protein function. PNAS vol. 107 no. 23 10555-10560 PMID: 20498049|
|13.||Liu Z, Farley A, Chen L, Kirby BJ, Kovacs CS, Blackburn C, Manley N. (2010) Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions. PLoS Genetics 6(12): e1001251 PMID: 21203493|
|14.||Chen L, Xiao S, Manley N. (2009) Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 113(3):567-74 PMID: 18978204|
|15.||Wang ZR, Guo L, Chen L, McEachern MJ. (2009) Evidence for an additional base-pairing element between the telomeric repeat and the telomerase RNA template in Kluyveromyces lactis and other yeasts. Mol Cell Bio. 29(20):5389-98 PMID: 19687297|
|16.||Liu X, Chen Y, Zhang F, Chen L, Ha T, Gao X, Li C. (2007) Synergistically therapeutic effects of VEGF165 and angiopoietin-1 on ischemic rat myocardium. Scand Cardiovasc J. 41(2):95-101 PMID: 17454834|
|17.||Zhang F, Yang Z, Chen Y, Qin J, Zhu T, Xu D, Xu Z, Xu Q, Qian Y, Ma W, Chen L, Gao X, Li C, Ha T, Kao RL. (2003) Clinical cellular cardiomyoplasty: technical considerations. J Card Surg. 18(3):268-73 PMID: 12809404|
|18.||Chen L, Gao X. Neuronal apoptosis induced by endoplasmic reticulum stress. (2002) Neurochem Res. 27(9):891-8 PMID: 12396099|
|19.||Jiang P, Chen L, Lin J, Liu Q, Ding J, Gao X, Guo Z. (2002) Novel zinc fluorescent probe bearing dansyl and aminoquinoline groups. Chem Commun (Camb). (13):1424-5 PMID: 12125585|