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51. Genomic analysis of the telomeric length effect on organismic lifespan in Caenorhabditis elegans

Author

Taesung Park, Moon Cheol Park, Daechan Park, Junho Lee, and Eunkyung Lee

Subjects
Longevity, Ribonuclease H, Biophysics, Biochemistry, Genome, RNA interference, Gene expression, Daf-16, Animals, Intestinal Mucosa, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Molecular Biology, Gene, Genetics, biology, Forkhead Transcription Factors, Genomics, Cell Biology, Telomere, biology.organism_classification, Nucleotidyltransferases, Up-Regulation, Gene Expression Regulation, DNA microarray, Transcription Factors
Abstract

Telomeres are multifunctional elements that protect chromosomal ends. Telomere length affects lifespan and stress resistance. In our previous report, we found that the increase of telomere length extended organismic lifespan in Caenorhabditis elegans. To investigate the effect of the telomere length on organismic lifespan at the global gene expression level, we performed microarray experiments using mRNA from long telomere-containing worms. We identified genes that showed significant difference in transcript levels from long telomere-containing worms. We examined the expression patterns of these genes and measured lifespan of the worms over-expressing each of the up-regulated genes. Most up-regulated genes, when over-expressed, extended lifespan of C. elegans. In particular, over-expression of rnh-1.3 in the intestine extended lifespan in the daf-16-dependent manner and increased stress resistance. Interestingly, genes up-regulated in long telomeric worms partially overlapped with the genes whose transcription was increased by the rde-3 mutations, and the over-expression of each of these genes also extended the longevity of worms, raising the possibility that the telomere effect may involve molecular players shared with the RNAi machinery.

Published
2010

52. New insights into rheumatoid arthritis by whole transcriptome profiling of autoreactive B cells

Author

Ankit Mahendra, Xingyue Yang, Peng Qiu, Daechan Park, Cristian Coarfa, Sandeep K Agarwal, and Navin Varadarajan

Subjects
Immunology, Immunology and Allergy
Abstract

B cells are important in the pathogenesis of rheumatoid arthritis (RA). By utilizing a flow-cytometric assay to reliably detect the low frequency of autoreactive B cells (ABC) in the blood of RA patients, we performed RNA sequencing of citrulline-specific ABCs and compared them with hemaglutinin (HA) specific B cells. To the best of our knowledge, this is the first complete transcriptome map of human ABCs in autoimmunity, and our data shows a specific up regulation of amphiregulin (AREG) (q-value = 3.1×10−12, fold-change = 250); a member of the EGF growth factor of ligands. Also, the receptor signaling pathways associated with AREG including EGF mediated signaling (FDR q-value = 0.06) and the NRG1 mediated signaling (FDR q-value = 0.03) were enriched, supporting an important role for AREG. Consistent with the well-recognized role of TNF in RA, our RNA-seq data revealed highly significant enrichment of both the TNF pathway (FDR q-value = 0.02) and genes that are targets of TNF (FDR q-value = 0.08) in ABCs from RA patients. Comparisons of our differential expression gene analyses with known risk loci of RA (SNPs) identified genes with decreased expression including TNFAIP3 (leading to inflammatory responses), and REL (anti-apoptotic); and increased expression including CCR6 (maturation and differentiation), and ETS1 (development and maturation) within ABCs than HA specific B cells. Ig sequencing of ABC show normal mutational targeting frequencies but increased somatic hymermutation. In aggregate, our results indicate that the pro-inflammatory nature of IL15 and TNF mediated signaling might promote a feed-forward loop promoting the altered differentiation of ABCs through the AREG-TNF signaling axis, which in turn promotes inflammation.

Published
2016

53. Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires.

Author

DeKosky, Brandon J., Lungu, Oana I., Daechan Park, Johnson, Erik L., Charab, Wissam, Chrysostomou, Constantine, Kuroda, Daisuke, Ellington, Andrew D., Ippolito, Gregory C., Gray, Jeffrey J., and Georgiou, George

Subjects
ANTIGENS, IMMUNOGLOBULINS, B cells, IMMUNITY, IMMUNE response
Abstract

Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy- and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19+CD20+CD27- IgM-naive B cells, >120,000 antibody clusters from CD19+CD20+CD27+ antigen- experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ-Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease. [ABSTRACT FROM AUTHOR]

Published
2016
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54. Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans.

Author

Jiwon Jung, Mundle, Sophia T., Ustyugova, Irina V., Horton, Andrew P., Boutz, Daniel R., Pougatcheva, Svetlana, Prabakaran, Ponraj, McDaniel, Jonathan R., King, Gregory R., Daechan Park, Person, Maria D., Congxi Ye, Bing Tan, Yuri Tanno, Jin Eyun Kim, Curtis, Nicholas C., DiNapoli, Joshua, Delagrave, Simon, Ross, Ted M., and Ippolito, Gregory C.

Subjects
*VIRAL proteins, *INFLUENZA vaccines, *GLYCANS, *OLDER people, *SEASONAL influenza, *INFLUENZA prevention, *EGGS, *POLYSACCHARIDES, *ANTIGEN-antibody reactions, *RESEARCH, *IMMUNIZATION, *IMMUNOGLOBULINS, *AGE distribution, *ANIMAL experimentation, *RESEARCH methodology, *MONOCLONAL antibodies, *MEDICAL cooperation, *EVALUATION research, *COMPARATIVE studies, *INFLUENZA, *RESEARCH funding, *VIRAL antibodies, *LONGITUDINAL method, *INFLUENZA A virus, H1N1 subtype, *INFLUENZA A virus, H3N2 subtype
Abstract

Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza. [ABSTRACT FROM AUTHOR]

Published
2021
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