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Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

dc.contributor.authorJury N.
dc.contributor.authorAbarzua S.
dc.contributor.authorDiaz I.
dc.contributor.authorGuerra M.V.
dc.contributor.authorAmpuero E.
dc.contributor.authorCubillos P.
dc.contributor.authorMartinez P.
dc.contributor.authorHerrera-Soto A.
dc.contributor.authorArredondo C.
dc.contributor.authorRojas F.
dc.contributor.authorManterola M.
dc.contributor.authorRojas A.
dc.contributor.authorMontecino M.
dc.contributor.authorVarela-Nallar L.
dc.contributor.authorVan Zundert B.
dc.date.accessioned2020-09-02T22:21:03Z
dc.date.available2020-09-02T22:21:03Z
dc.date.issued2020
dc.identifier10.1186/s13148-020-0816-9
dc.identifier.citation12, 1, -
dc.identifier.issn18687075
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4989
dc.descriptionBackground: Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results: Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions: Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD. © 2020 The Author(s).
dc.language.isoen
dc.publisherBioMed Central Ltd.
dc.subjectALS
dc.subjectAstrocyte
dc.subjectBrain
dc.subjectFTD
dc.subjectH3K9me3
dc.subjectMemory
dc.subjectNeuron
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectArticle
dc.subjectastrocyte
dc.subjectC9ORF72 gene
dc.subjectcognitive defect
dc.subjectdentate gyrus
dc.subjectepigenetics
dc.subjectgene
dc.subjectgene silencing
dc.subjecthippocampal CA1 region
dc.subjecthippocampal CA3 region
dc.subjecthistone methylation
dc.subjectmotor cortex
dc.subjectmouse
dc.subjectnonhuman
dc.subjectpriority journal
dc.subjectspinal cord
dc.titleWidespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice
dc.typeArticle


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