The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression

Haploinsufficiency of SETD5 is implicated in syndromic autism spectrum disorder (ASD), but the molecular mechanism underlying the pathological role of this protein has remained unclear. We have now shown that Setd5+/– mice manifest ASD-related behavioral phenotypes and that the expression of ribosom...

Full description

Saved in:
Bibliographic Details
Published iniScience Vol. 23; no. 4; p. 101030
Main Authors Nakagawa, Tadashi, Hattori, Satoko, Nobuta, Risa, Kimura, Ryuichi, Nakagawa, Makiko, Matsumoto, Masaki, Nagasawa, Yuko, Funayama, Ryo, Miyakawa, Tsuyoshi, Inada, Toshifumi, Osumi, Noriko, Nakayama, Keiichi I., Nakayama, Keiko
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.04.2020
Elsevier
Subjects
Behavior Genetics
Behavioral Neuroscience
Molecular Genetics
Molecular Neuroscience
Behavioral Neuroscience
Molecular Genetics
Behavior Genetics
Molecular Neuroscience
Online AccessGet full text

Cover

More Information
Summary:Haploinsufficiency of SETD5 is implicated in syndromic autism spectrum disorder (ASD), but the molecular mechanism underlying the pathological role of this protein has remained unclear. We have now shown that Setd5+/– mice manifest ASD-related behavioral phenotypes and that the expression of ribosomal protein genes and rDNA is disturbed in the brain of these mice. SETD5 recruited the HDAC3 complex to the rDNA promoter, resulting in removal of the histone mark H4K16ac and its reader protein TIP5, a repressor of rDNA expression. Depletion of SETD5 attenuated rDNA expression, translational activity, and neural cell proliferation, whereas ablation of TIP5 in SETD5-deficient cells rescued these effects. Translation of cyclin D1 mRNA was specifically down-regulated in SETD5-insufficient cells. Our results thus suggest that SETD5 positively regulates rDNA expression via an HDAC3-mediated epigenetic mechanism and that such regulation is essential for translation of cyclin D1 mRNA and neural cell proliferation. [Display omitted] •Setd5+/– mice manifest syndromic autism-related phenotypes•SETD5 recruits the HDAC3 complex to the rDNA promoter•SETD5 deficiency reduces rRNA abundance and attenuates translational activity•SETD5 deficiency inhibits cyclin D1 mRNA translation and neural cell proliferation Behavior Genetics; Molecular Genetics; Behavioral Neuroscience; Molecular Neuroscience
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Lead Contact
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.101030