Epigenetics of Renal Development and Disease

Abstract

An understanding of epigenetics is indispensable to our understanding of gene regulation under normal and pathological states. This knowledge will help with designing better therapeutic approaches in regenerative tissue medicine. Epigenetics allows us to parse out the mechanisms by which transcriptional regulators gain access to specific gene loci thereby imprinting epigenetic information affecting chromatin function. This epigenetic memory forms the basis of cell lineage specification in multicellular organisms. Post-translational modifications to DNA and histones in the nucleosome core form characteristic epigenetic codes which are distinct for self-renewing and primed progenitor cell populations. Studies of chromatin modifiers and modifications in renal development and disease have been gaining momentum. Both congenital and adult renal diseases have a gene-environment component, which involves alterations to the epigenetic information imprinted during development. This epigenetic memory must be characterized to establish optimal treatment of both acute and chronic renal diseases.

Keywords: Epigenetics; HATs; HDACs; Kidney; bivalent histone code; chromatin modifiers; histone modifications; kidney disease; nephron progenitors.

Figure 1

Renal cell fate is influenced by epigenetic modifications. (A) Specification of the nephric duct and renal epithelia requires the recruitment of the MLL complex by Pax2 via the PTIP adapter protein. (B) Loss of bivalent epigenetic code in nephron-fated induced mesenchyme. The cap mesenchyme represents the progenitors of all nephrons in the kidney. The promoters of lineage specific genes in this cell population are bivalent and carry both activation (H3K4me3) and repressive (H3K9me3, H3K27me3) methylation marks. Upon commitment to the formation of nephrons the promoters of renal-lineage genes lose the repressive marks (H3K9me3 and H3K27me3). The expression of lysine methyl transferases (Ash2l, G9a, Ezh2 and Suz12) coincide with that of their corresponding epigenetic modifications.

Figure 2

Reciprocal nature of H3K4me and H3K79me expression during development. The H3K4me3 marks are more abundant in the prenatal phase of the developing kidney while H3K79me3 levels increase during postnatal development of the kidney.