NIH Training Grant Fellow: Clayton White

Clayton White

Clayton White is a Ph.D. candidate in the Casali lab at UC Irvine. His passion for biology began as an undergraduate researcher investigating the anti-microbial properties of an ocular peptide in the McKown lab at James Madison University in Virginia.

His thesis work in the Casali lab is focused on investigating the molecular mechanisms underpinning immunoglobulin class switch DNA recombination (CSR), somatic hypermutation (SHM) and the regulation of the antibody response. CSR and SHM alter the antibody isotype and enhance the antibody's affinity for antigen, respectively. CSR entails a DNA recombination event in which an upstream constant heavy (CH) chain exon, such as Cμ is replaced with a downstream (CH) chain exon, such as Cγ1, resulting in CSR from IgM to IgG1. SHM introduces mainly point mutations into the antibody variable region loci to provide the structural substrate for selection of higher affinity mutants by antigen. Both SCR and SHM are initiated by activation-induced cytidine deaminase (AID), which introduces DNA lesions in the IgH locus.

Clayton’s earliest work in the Casali lab focused on the critical role that AID plays in the development of lupus and hematologic cancer. Clayton hypothesized that the transcription factor HoxC4, which is upregulated by estrogen and regulates AID expression, would be elevated in lupus. Indeed, Clayton found that both HoxC4 and AID were upregulated in lupus patients and lupus-prone MRL/Faslpr/lpr mice.

Clayton then showed that HoxC4 deficiency resulted in decreased AID expression, autoantibody levels and kidney pathology in MRL/Faslpr/lpr mice. Further, HoxC4 deficiency decreased the frequency of interchromosomal c-Myc/IgH translocations in MRL/Faslpr/lpr mice, which contribute to lymphomagenesis (Autoimmunity 44: 585-598, 2011). Collectively, these results suggest that estrogen regulation in lupus patients, which are predominantly females, may be useful in ameliorating lupus disease and in preventing interchromosomal translocations that are possibly responsible for the increased frequency of B cell lymphomas in lupus patients.

Clayton then turned his attention to the role of Rev1, a translesion DNA synthesis (TLS) polymerase, in CSR. He found that Rev1 was involved in the same pathway of CSR as Ung, a critical component of the CSR machinery. He demonstrated a novel, non-enzymatic scaffold function for Rev1 during CSR and provided a new paradigmatic role for TLS polymerases in the dynamics of the IgH locus in his most recently published work (Cell Rep. 2: 1220-1232, 2012).

Clayton’s current interests are to investigate the role of epigenetic modifications in the antibody response and lupus. He is interested in the role of histone acetylation and microRNAs in the development of class-switched antibody responses, which are critical for immunity to pathogens and the development of autoimmunity. Outside of lab Clayton serves as a Graduate InterConnect Peer Mentor for international graduate students and enjoys sports, the outdoors, music and cooking.

Honors:

NIH NIAID T32 Immunology Research Training Program (5T32 AI060573), UC Irvine (selected for two consecutive years from 2011 to 2013).

Second place award for poster presentation: Rev1 recruits Ung to switch regions and enhances dU glycosylation for immunoglobulin class switch DNA recombination. 10th UC Irvine Immunology Fair (2012).

Second place award for oral presentation: The translesion DNA synthesis polymerase Rev1 recruits Ung for immunoglobulin class switch DNA recombination. 9th UC Irvine Immunology Fair (2011).

Dr. William F. Holcomb Scholarship (In recognition of outstanding research in Biomedical Sciences), UC Irvine (2011).

UC Irvine - Howard Hughes Medical Institute (HHMI) Graduate Fellow, UC Irvine (2010 to 2011).

Publications:

Zan, H.*, C. A. White*, L. M. Thomas, J. Zhang, G. Li, E. S. Yu, Z. Xu, T. Mai and P. Casali. 2012. Rev1 recruits Ung to switch regions and enhances dU glycosylation for immunoglobulin class switch DNA recombination. Cell REPORTS 2: 1220-1232. *Equal contributors.

Pone, E. J., J. Zhang, T. Mai, C. A. White, G. Li, J. K. Sakakura, P. J. Patel, A. Al-Qahtani, H. Zan, Z. Xu and P. Casali. 2012. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway. Nature Commun. 3: 767.

Pone, E. J., Z. Xu, C. A. White, H. Zan and P. Casali. 2011. B cell TLRs and induction of immunoglobulin class-switch DNA recombination.Front. Biosci. 17: 2594-2615.

White, C. A., J. Hawkins, E. J. Pone, E. Yu, A. Al-Qahtani, T. Mai, H. Zan, and P. Casali. 2011. AID dysregulation in lupus-prone MRL/Faslpr/lprmice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgHloci translocations: Modulation by HoxC4.Autoimmunity. 44: 585-598.

Zan, H., J. Zhang, A. Al-Qahtani, E. J. Pone, C. A. White, D. Lee, L. Yel, T. Mai, and P. Casali. 2011. Endonuclease G plays a role in immunoglobulin class switch DNA recombination by introducing double-strand breaks in switch regions. Mol. Immunol. 48: 610-622.

Xu, Z., Z. Fulop, G. Wu, S.-R. Park, J. Zhang, E. J. Pone, A. Al-Qahtani, C. A. White, T. Mai, L.M. Thomas, P. Steinacker, Z. Li, J. R. Yates, III, B. Herron, M. Otto, H. Zan, H. Fu and P. Casali. 2010. 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nature Struct. & Mol. Biol. 17: 1124-1135.