2008-2013 PhD in Biochemistry and Molecular Biology, Joan and Ronald Conaway laboratory, Stowers Institute for Medical Research/ University of Kansas Medical Center.
Thesis: Structural and functional analysis on human INO80 chromatin remodeling complexes
2013-2016 Postdoc in Department of Biochemistry/Department of Medicine-Hematology Division, Steven Artandi laboratory, Stanford University

Current Role at Stanford

Postdoctoral Fellow

Honors & Awards

  • Career-transitioning Fellowship Award, Stanford Cancer Institute (July 1, 2018)


All Publications

  • Loss of human TGS1 hypermethylase promotes increased telomerase RNA and telomere elongation Cell Reports Chen, L., Roake, C. M., Galati, A., Bavasso, F., Micheli, E., Saggio, I., Schoeftner, S., Cacchione, S., Gatti, M., Artandi, S. E., Raffa, G. D. 2020: 1358-1372
  • An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1. Cell Chen, L., Roake, C. M., Freund, A., Batista, P. J., Tian, S., Yin, Y. A., Gajera, C. R., Lin, S., Lee, B., Pech, M. F., Venteicher, A. S., Das, R., Chang, H. Y., Artandi, S. E. 2018


    Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains-a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly. Instead, TCAB1 inactivation causes unfolding of CR4/5 helices that are required for catalysis and for association with the telomeraseáreverse-transcriptase (TERT). CR4/5 mutations derived from patients with telomere biology disorders provoke defects in catalysis and TERT binding similar to TCAB1 inactivation. These findings reveal a conformational "activity switch" in human telomerase RNA controlling catalysis and TERT engagement. The identification of two discrete catalytic states for telomerase suggests an intramolecular means for controlling telomerase in cancers and progenitor cells.

    View details for PubMedID 29804836

  • Biochemical assays for analyzing activities of ATP-dependent chromatin remodeling enzymes. Journal of visualized experiments : JoVE Chen, L., Ooi, S. K., Conaway, J. W., Conaway, R. C. 2014

    View details for DOI 10.3791/51721

  • Generation and purification of human INO80 chromatin remodeling complexes and subcomplexes. Journal of visualized experiments : JoVE Chen, L., Ooi, S. K., Conaway, R. C., Conaway, J. W. 2014

    View details for DOI 10.3791/51720

  • Multiple modes of regulation of the human Ino80 SNF2 ATPase by subunits of the INO80 chromatin-remodeling complex. Proceedings of the National Academy of Sciences of the United States of America Chen, L., Conaway, R. C., Conaway, J. W. 2013; 110 (51): 20497?502


    SNF2 family ATPases are ATP-dependent motors that often function in multisubunit complexes to regulate chromatin structure. Although the central role of SNF2 ATPases in chromatin biology is well established, mechanisms by which their catalytic activities are regulated by additional subunits of chromatin-remodeling complexes are less well understood. Here we present evidence that the human Inositol auxotrophy 80 (Ino80) SNF2 ATPase is subject to regulation at multiple levels in the INO80 chromatin-remodeling complex. The zinc finger histidine triad domain-containing protein Ies2 (Ino Eighty Subunit 2) functions as a potent activator of the intrinsic catalytic activity of the Ino80 ATPase, whereas the YL-1 family Ies6 (Ino Eighty Subunit 6) and actin-related Arp5 proteins function together to promote binding of the Ino80 ATPase to nucleosomes. These findings support the idea that both substrate recognition and the intrinsic catalytic activities of SNF2 ATPases have evolved as important sites for their regulation.

    View details for DOI 10.1073/pnas.1317092110

    View details for PubMedID 24297934

  • Subunit Organization of the Human INO80 Chromatin Remodeling Complex AN EVOLUTIONARILY CONSERVED CORE COMPLEX CATALYZES ATP-DEPENDENT NUCLEOSOME REMODELING JOURNAL OF BIOLOGICAL CHEMISTRY Chen, L., Cai, Y., Jin, J., Florens, L., Swanson, S. K., Washburn, M. P., Conaway, J. W., Conaway, R. C. 2011; 286 (13): 11283-11289


    We previously identified and purified a human ATP-dependent chromatin remodeling complex with similarity to the Saccharomyces cerevisiae INO80 complex (Jin, J., Cai, Y., Yao, T., Gottschalk, A. J., Florens, L., Swanson, S. K., Gutierrez, J. L., Coleman, M. K., Workman, J. L., Mushegian, A., Washburn, M. P., Conaway, R. C., and Conaway, J. W. (2005) J. Biol. Chem. 280, 41207-41212) and demonstrated that it is composed of (i) a Snf2 family ATPase (hIno80) related in sequence to the S. cerevisiae Ino80 ATPase; (ii) seven additional evolutionarily conserved subunits orthologous to yeast INO80 complex subunits; and (iii) six apparently metazoan-specific subunits. In this report, we present evidence that the human INO80 complex is composed of three modules that assemble with three distinct domains of the hIno80 ATPase. These modules include (i) one that is composed of the N terminus of the hIno80 protein and all of the metazoan-specific subunits and is not required for ATP-dependent nucleosome remodeling; (ii) a second that is composed of the hIno80 Snf2-like ATPase/helicase and helicase-SANT-associated/post-HSA (HSA/PTH) domain, the actin-related proteins Arp4 and Arp8, and the GLI-Kruppel family transcription factor YY1; and (iii) a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5. Through purification and characterization of hINO80 complex subassemblies, we demonstrate that ATP-dependent nucleosome remodeling by the hINO80 complex is catalyzed by a core complex comprising the hIno80 protein HSA/PTH and Snf2 ATPase domains acting in concert with YY1 and the complete set of its evolutionarily conserved subunits. Taken together, our findings shed new light on the structure and function of the INO80 chromatin-remodeling complex.

    View details for DOI 10.1074/jbc.M111.222505

    View details for Web of Science ID 000288797100040

    View details for PubMedID 21303910

  • Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease Molecular Cell Roake, C. M., Chen, L., Chakravarthy, A., Raffa, G. D., Ferrell, Jr., J. E., Artandi, S. E. 2019
  • Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature Lin, S., Nascimento, E. M., Gajera, C. R., Chen, L., Neuh÷fer, P., Garbuzov, A., Wang, S., Artandi, S. E. 2018


    Hepatocytes are replenished gradually during homeostasis and robustly after liver injury1, 2. In adults, new hepatocytes originate from the existing hepatocyte pool3-8, but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases9-11. Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice, we demonstrate that rare hepatocytes with high telomerase expression (TERTHighhepatocytes) are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERTHighhepatocytes is accelerated and their progeny cross zonal boundaries. RNA sequencing shows that metabolic genes are downregulated in TERTHighhepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERTHighhepatocytes combined with chemical injury causes a marked increase in stellate cell activation and fibrosis. These results provide support for a 'distributed model' of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass.

    View details for PubMedID 29618815

  • Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. Proceedings of the National Academy of Sciences of the United States of America Wang, L., Limbo, O., Fei, J., Chen, L., Kim, B., Luo, J., Chong, J., Conaway, R. C., Conaway, J. W., Ranish, J. A., Kadonaga, J. T., Russell, P., Wang, D. 2014; 111 (52): 18566-18571


    CSB/ERCC6 (Cockayne syndrome B protein/excision repair cross-complementation group 6), a member of a subfamily of SWI2/SNF2 (SWItch/sucrose nonfermentable)-related chromatin remodelers, plays crucial roles in gene expression and the maintenance of genome integrity. Here, we report the mechanism of the autoregulation of Rhp26, which is the homolog of CSB/ERCC6 in Schizosaccharomyces pombe. We identified a novel conserved protein motif, termed the "leucine latch," at the N terminus of Rhp26. The leucine latch motif mediates the autoinhibition of the ATPase and chromatin-remodeling activities of Rhp26 via its interaction with the core ATPase domain. Moreover, we found that the C terminus of the protein counteracts this autoinhibition and that both the N- and C-terminal regions of Rhp26 are needed for its proper function in DNA repair in vivo. The presence of the leucine latch motif in organisms ranging from yeast to humans suggests a conserved mechanism for the autoregulation of CSB/ERCC6 despite the otherwise highly divergent nature of the N- and C-terminal regions.

    View details for DOI 10.1073/pnas.1420227112

    View details for PubMedID 25512493

  • Role for human mediator subunit MED25 in recruitment of mediator to promoters by endoplasmic reticulum stress-responsive transcription factor ATF6a. journal of biological chemistry Sela, D., Conkright, J. J., Chen, L., Gilmore, J., Washburn, M. P., Florens, L., Conaway, R. C., Conaway, J. W. 2013; 288 (36): 26179-26187


    Transcription factor ATF6? functions as a master regulator of endoplasmic reticulum (ER) stress response genes. In response to ER stress, ATF6? translocates from its site of latency in the ER membrane to the nucleus, where it activates RNA polymerase II transcription of ER stress response genes upon binding sequence-specifically to ER stress response enhancer elements (ERSEs) in their promoter-regulatory regions. In a recent study, we demonstrated that ATF6? activates transcription of ER stress response genes by a mechanism involving recruitment to ERSEs of the multisubunit Mediator and several histone acetyltransferase (HAT) complexes, including Spt-Ada-Gcn5 (SAGA) and Ada-Two-A-containing (ATAC) (Sela, D., Chen, L., Martin-Brown, S., Washburn, M.P., Florens, L., Conaway, J.W., and Conaway, R.C. (2012) J. Biol. Chem. 287, 23035-23045). In this study, we extend our investigation of the mechanism by which ATF6? supports recruitment of Mediator to ER stress response genes. We present findings arguing that Mediator subunit MED25 plays a critical role in this process and identify a MED25 domain that serves as a docking site on Mediator for the ATF6? transcription activation domain.

    View details for DOI 10.1074/jbc.M113.496968

    View details for PubMedID 23864652

  • Endoplasmic Reticulum Stress-responsive Transcription Factor ATF6 alpha Directs Recruitment of the Mediator of RNA Polymerase II Transcription and Multiple Histone Acetyltransferase Complexes JOURNAL OF BIOLOGICAL CHEMISTRY Sela, D., Chen, L., Martin-Brown, S., Washburn, M. P., Florens, L., Conaway, J. W., Conaway, R. C. 2012; 287 (27): 23035-23045


    The basic leucine zipper transcription factor ATF6? functions as a master regulator of endoplasmic reticulum (ER) stress response genes. Previous studies have established that, in response to ER stress, ATF6? translocates to the nucleus and activates transcription of ER stress response genes upon binding sequence specifically to ER stress response enhancer elements in their promoters. In this study, we investigate the biochemical mechanism by which ATF6? activates transcription. By exploiting a combination of biochemical and multidimensional protein identification technology-based mass spectrometry approaches, we have obtained evidence that ATF6? functions at least in part by recruiting to the ER stress response enhancer elements of ER stress response genes a collection of RNA polymerase II coregulatory complexes, including the Mediator and multiple histone acetyltransferase complexes, among which are the Spt-Ada-Gcn5 acetyltransferase (SAGA) and Ada-Two-A-containing (ATAC) complexes. Our findings shed new light on the mechanism of action of ATF6?, and they outline a straightforward strategy for applying multidimensional protein identification technology mass spectrometry to determine which RNA polymerase II transcription factors and coregulators are recruited to promoters and other regulatory elements to control transcription.

    View details for DOI 10.1074/jbc.M112.369504

    View details for Web of Science ID 000306495000060

    View details for PubMedID 22577136

  • Cholesterol-dependent and - Independent CD40 internalization and signaling activation in cardiovascular endothelial cells ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chen, J., Chen, L., Wang, G., Tang, H. 2007; 27 (9): 2005-2013


    It remains elusive how CD40 endocytosis or clustering on the cell surface is induced by different forms of CD40 agonist. This study aims to investigate whether lipid rafts differentially regulate CD40 traffic and signaling in proinflammatory activation of cardiovascular endothelial cells (ECs).Using fluorescent microscopy and flow cytometry, we demonstrated that soluble CD40L and agonistic antibody G28.5 induced CD40 internalization via clathrin-independent pathway. Furthermore, depletion of cholesterol by methyl-beta-cyclodextrin (MCD) or siRNA knockdown of caveolin-1 efficiently blocked CD40 internalization, suggesting that caveolae-rafts pathway regulates CD40 internalization. In contrast, a membrane-bound CD40L mimic (megamer) triggered aggregation of CD40 rafts outside of the conventional cholera toxin B subunit-positive lipid rafts resistant to cholesterol depletion. Finally, both G28.5 and megamer induced CD40 translocation to Brij58-insoluble, low buoyant density rafts, a movement insensitive to cholesterol depletion. However, MCD effectively inhibited G28.5 but not megamer-induced CD40 activation, and such inhibition could be alleviated by cholesterol reconstitution, suggesting that 2 different raft structures of CD40 induced by G28.5 or megamer possess differential sensitivity to cellular cholesterol levels in downstream signaling.Depending on different forms of agonist, CD40 uses either a cholesterol-dependent or -independent mode for trafficking and signaling in ECs.

    View details for DOI 10.1161/ATVBAHA.107.145961

    View details for Web of Science ID 000249084700021

    View details for PubMedID 17626904

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