MOF maintains transcriptional programs regulating cellular stress response

Oncogene. 2016 May;35(21):2698-710. doi: 10.1038/onc.2015.335. Epub 2015 Sep 21.

Abstract

MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Histone Acetyltransferases / genetics*
  • Histone Acetyltransferases / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Podocytes / cytology
  • Podocytes / metabolism
  • Podocytes / physiology
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / metabolism
  • Stress, Physiological / genetics*
  • Transcription, Genetic

Substances

  • Heat-Shock Proteins
  • Nuclear Proteins
  • SCARA3 protein, human
  • Scavenger Receptors, Class A
  • Histone Acetyltransferases
  • KAT8 protein, human
  • MOF protein, mouse