Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease.
Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases.
Osorio
Fernando G
FG
Departamento de Bioquímica y Biología Molecular Unidad de Epigenética, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
Varela
Ignacio
I
Lara
Ester
E
Puente
Xose S
XS
Espada
Jesús
J
Santoro
Raffaella
R
Freije
José M P
JM
Fraga
Mario F
MF
López-Otín
Carlos
C
D000375:Aging / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D008565:Membrane Proteins / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D045726:Metalloproteases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009685:Nuclear Envelope / Q000201:enzymology* / Q000378:metabolism
D008565:Membrane Proteins; D045726:Metalloproteases; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse