Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin.
Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer's disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.
Université Paris Descartes, Centre Interdisciplinaire Chimie Biologie-Paris, Inserm UMRS1007, Paris, France.
Zeyni
Z
Mansuroglu
Université Paris Descartes, Centre Interdisciplinaire Chimie Biologie-Paris, Inserm UMRS1007, Paris, France.
Houda
H
Benhelli-Mokrani
Université Paris Descartes, Centre Interdisciplinaire Chimie Biologie-Paris, Inserm UMRS1007, Paris, France.
Vasco
V
Marcato
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Audrey
A
Sultan
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Marie
M
Violet
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Alban
A
Chauderlier
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Lucie
L
Delattre
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Anne
A
Loyens
Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, Lille, France.
Smail
S
Talahari
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Séverine
S
Bégard
Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, Lille, France.
Fabrice
F
Nesslany
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Morvane
M
Colin
Université Paris Descartes, Centre Interdisciplinaire Chimie Biologie-Paris, Inserm UMRS1007, Paris, France.
Sylvie
S
Souès
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Bruno
B
Lefebvre
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Luc
L
Buée
Université de Lille, Inserm, CHU-Lille, UMRS1172, Alzheimer &Tauopathies, Lille, France.
Marie-Christine
MC
Galas
Université Paris Descartes, Centre Interdisciplinaire Chimie Biologie-Paris, Inserm UMRS1007, Paris, France.
Eliette
E
Bonnefoy
D000818:Animals; D001921:Brain / Q000378:metabolism; D002503:Centromere / Q000235:genetics*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D016875:tau Proteins; D000090266:Chromobox Protein Homolog 5; D008239:Lysine