Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin

Zeyni Mansuroglu (1) , Houda Benhelli-Mokrani (1) , Vasco Marcato (1) , Audrey Sultan (2) , Marie Violet (2) , Alban Chauderlier (2) , Lucie Delattre (2) , Anne Loyens (2) , Smail Talahari (3) , Séverine Bégard (2) , Fabrice Nesslany (3) , Morvane Colin (2) , Sylvie Souès (1) , Bruno Lefebvre (2) , Luc Buée (2) , Marie-Christine Galas (2) , Eliette Bonnefoy (1)

1 CICB-Paris FR3567 - Centre interdisciplinaire chimie biologie-Paris
2 Alzheimer & Tauopathies [JPArc]
3 Laboratoire de toxicologie génétique [Lille]

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.

Domaines: Neurobiologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Médecine humaine et pathologie

Zeyni Mansuroglu, Houda Benhelli-Mokrani, Vasco Marcato, Audrey Sultan, Marie Violet, et al.. Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin. Scientific Reports, 2016, 6 (1), pp.33047. ⟨10.1038/srep33047⟩. ⟨hal-03093346⟩