4.7 Article

Altered activity-regulated H3K9 acetylation at TGF-beta signaling genes during egocentric memory in Huntington's disease

Journal

PROGRESS IN NEUROBIOLOGY
Volume 219, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2022.102363

Keywords

Huntington?s disease; Striatum; Epigenomic; Histone acetylation; TGF-beta signaling; Egocentric memory

Categories

Funding

  1. CHDI Foundation, Inc, USA
  2. Agence Nationale de la Recherche, France [ANR-2017-CE12-0027]
  3. Centre National de la Recherche Scientifique, France (CNRS)
  4. University of Strasbourg, France
  5. ANR [ANR-2017-CE12-0027]
  6. IdEx fellowship program (Strasbourg, France)
  7. CHDI
  8. French government
  9. Association Huntington France (AHF)

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This study reveals the molecular mechanisms underlying cognitive deficits in Huntington's disease, including altered activity-dependent epigenetic gene reprogramming and compromised H3K9 acetylation and TGF beta signaling in the striatum.
Molecular mechanisms underlying cognitive deficits in Huntington's disease (HD), a striatal neurodegenerative disorder, are unknown. Here, we generated ChIPseq, 4Cseq and RNAseq data on striatal tissue of HD and control mice during striatum-dependent egocentric memory process. Multi-omics analyses showed altered activity -dependent epigenetic gene reprogramming of neuronal and glial genes regulating striatal plasticity in HD mice, which correlated with memory deficit. First, our data reveal that spatial chromatin re-organization and transcriptional induction of BDNF-related markers, regulating neuronal plasticity, were reduced since memory acquisition in the striatum of HD mice. Second, our data show that epigenetic memory implicating H3K9 acetylation, which established during late phase of memory process (e.g. during consolidation/recall) and contributed to glia-mediated, TGF beta-dependent plasticity, was compromised in HD mouse striatum. Specifically, memory-dependent regulation of H3K9 acetylation was impaired at genes controlling extracellular matrix and myelination. Our study investigating the interplay between epigenetics and memory identifies H3K9 acetylation and TGF beta signaling as new targets of striatal plasticity, which might offer innovative leads to improve HD.

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