MOF maintains transcriptional programs regulating cellular stress response

TY - JOUR

T1 - MOF maintains transcriptional programs regulating cellular stress response

AU - Sheikh, B N

AU - Bechtel-Walz, W

AU - Lucci, J

AU - Karpiuk, O

AU - Hild, I

AU - Hartleben, B

AU - Vornweg, J

AU - Helmstädter, M

AU - Sahyoun, A H

AU - Bhardwaj, V

AU - Stehle, T

AU - Diehl, S

AU - Kretz, O

AU - Voss, A K

AU - Thomas, T

AU - Manke, T

AU - Huber, T B

AU - Akhtar, A

PY - 2016/5

Y1 - 2016/5

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Cycle Checkpoints

KW - Heat-Shock Proteins

KW - Histone Acetyltransferases

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Nuclear Proteins

KW - Podocytes

KW - Scavenger Receptors, Class A

KW - Stress, Physiological

KW - Transcription, Genetic

KW - Journal Article

U2 - 10.1038/onc.2015.335

DO - 10.1038/onc.2015.335

M3 - SCORING: Journal article

C2 - 26387537

VL - 35

SP - 2698

EP - 2710

JO - ONCOGENE

JF - ONCOGENE

SN - 0950-9232

IS - 21

ER -