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Kidney Week

Abstract: TH-PO481

Profiling Histone Modifications in the Normal Mouse Kidney and After Unilateral Ureteric Obstruction

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Hewitson, Timothy D., The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  • Holt, Stephen G., The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  • Smith, Edward R., The Royal Melbourne Hospital, Melbourne, Victoria, Australia
Background

Post-translational modification of nucleosomal histones has emerged as a major determinant of chromatin structure and gene activity. In this study, we hypothesised that unilateral ureteric obstruction (UUO), a widely used model of tubulointerstitial injury, would be associated with a distinct pattern of histone (H) modifications (marks) in the kidney.

Methods

Mass spectrometry (MS) was used to profile 63 different histone marks, and their corresponding unmodified amino acid, in normal mouse kidneys and those after 10 days of UUO. A subsequent histochemical analysis further examined examples of specific marks that changed significantly after UUO, for which antisera are available. The distribution of marks was compared with markers of pathology and transcription.

Results

Histone marks were much more widely distributed and abundant in the normal kidney than usually appreciated. Although aggregate analysis of the MS results revealed net differences between control and UUO groups, residue-specific variations were subtle. Of 16/63 significant changes (P<0.05), only 8 were quantitatively different by more than 5%. Nevertheless, we identified several not usually examined in the kidney including marks in the globular domain of core histones (H3K79), linker histones (H1.4) and histone variants (H3.1K27, H3.3K27). In several cases there were complementary changes in different marks on the same amino acid. In situ staining showed compartment specific differences in the distribution of individual marks. Using H3K79Me2 as an example, mark enrichment was heterogeneous, but largely co-localised with tubular hypoxia and transcription, but not proliferation, apoptosis or interstitial pathology.

Conclusion

Our study highlights the importance of unbiased screening in examining histone marks. Simultaneous changes in multiple marks on the same amino acid are indicative of a coordinated histone mark signature. The heterogeneous enrichment of marks, even within the same tubule, highlights the importance of regulatory context.

Funding

  • Government Support - Non-U.S.