PUBLICATION

Wolf-Hirschhorn syndrome candidate 1-like 1 epigenetically regulates nephrin gene expression

Authors
Ito, Y., Katayama, K., Nishibori, Y., Akimoto, Y., Kudo, A., Kurayama, R., Hada, I., Takahashi, S., Kimura, T., Fukutomi, T., Katada, T., Suehiro, J., Beltcheva, O., Tryggvason, K., Yan, K.
ID
ZDB-PUB-170224-13
Date
2017
Source
American journal of physiology. Renal physiology   312(6): F1184-F1199 (Journal)
Registered Authors
Tryggvason, Karlynn
Keywords
epigenetics, gene regulation, nephrin, podocyte
MeSH Terms
  • Adaptor Proteins, Signal Transducing/genetics
  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Binding Sites
  • Cytoskeletal Proteins/genetics
  • Cytoskeletal Proteins/metabolism
  • Disease Models, Animal
  • Doxorubicin
  • Epigenesis, Genetic*
  • Gene Expression Regulation
  • Gene Expression Regulation, Enzymologic
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase/genetics*
  • Histone-Lysine N-Methyltransferase/metabolism
  • Histones/metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Male
  • Membrane Proteins/genetics*
  • Membrane Proteins/metabolism
  • Methylation
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nephrotic Syndrome/chemically induced
  • Nephrotic Syndrome/enzymology
  • Nephrotic Syndrome/genetics*
  • Nephrotic Syndrome/pathology
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Podocytes/enzymology*
  • Podocytes/pathology
  • Promoter Regions, Genetic
  • RNA Interference
  • Transfection
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
28228401 Full text @ Am. J. Physiol. Renal Physiol.
Abstract
Altered expression of nephrin underlies the pathophysiology of proteinuria in both congenital and acquired nephrotic syndrome. However, the epigenetic mechanisms of nephrin gene regulation remain elusive. Here, we show that Wolf-Hirschhorn syndrome candidate 1-like 1 long form (WHSC1L1-L) is a novel epigenetic modifier of nephrin gene regulation. WHSC1L1-L was associated with histone H3K4 and H3K36 in human embryonic kidney cells. WHSC1L1-L gene was expressed in the podocytes and functional protein product was detected in these cells. WHSC1L1-L was found to bind nephrin but not other podocyte specific gene promoters, leading to its inhibition/suppression, abrogating the stimulatory effect of WT1 and NF-kB. Gene knockdown of WHSC1L1-L in primary cultured podocytes accelerated the transcription of nephrin but not CD2AP. An in vivo zebrafish study involving the injection of Whsc1l1 mRNA into embryos demonstrated an apparent reduction of nephrin mRNA but not podocin and CD2AP mRNA. Immunohistochemistry showed that both WHSC1L1-L and nephrin emerged at the S-shaped body stage in glomeruli. Immunofluorescence and confocal microscopy displayed WHSC1L1 to colocalize with trimethylated H3K4 in the glomerular podocytes. Chromatin immunoprecipitation assay revealed the reduction of the association of trimethylated H3K4 at the nephrin promoter regions. Finally, nephrin mRNA was upregulated in the glomerulus at the early proteinuric stage of mouse nephrosis, which was associated with the reduction of WHSC1L1. In conclusion, our results demonstrate that WHSC1L1-L acts as a histone methyltransferase in podocytes and regulates nephrin gene expression, which may in turn contribute to the integrity of the slit diaphragm of the glomerular filtration barrier.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping