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TIP60/KAT5 is required for neuronal viability in hippocampal CA1.


ABSTRACT: Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of ?-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.

SUBMITTER: Urban I 

PROVIDER: S-EPMC6838100 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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TIP60/KAT5 is required for neuronal viability in hippocampal CA1.

Urban Inga I   Kerimoglu Cemil C   Sakib M Sadman MS   Wang Haifang H   Benito Eva E   Thaller Christina C   Zhou Xunlei X   Yan Jun J   Fischer André A   Eichele Gregor G  

Scientific reports 20191107 1


Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plast  ...[more]

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