KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism in neurons

被引：1

作者：

Yheskel, Matanel ^{[1
]}

Hatch, Hayden A. M. ^{[2
]}

Pedrosa, Erika ^{[3
]}

Terry, Bethany K. ^{[1
]}

Siebels, Aubrey A. ^{[2
]}

Zheng, Xiang Yu ^{[1
]}

Blok, Laura E. R. ^{[4
]}

Fenckova, Michaela ^{[4
,5
]}

Sidoli, Simone ^{[6
]}

Schenck, Annette ^{[4
]}

Zheng, Deyou ^{[1
,2
,7
]}

Lachman, Herbert M. ^{[1
,2
,3
,8
]}

Secombe, Julie ^{[1
,2
]}

机构：

[1] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA

[2] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA

[3] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10461 USA

[4] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Human Genet, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[5] Univ South Bohemia, Fac Sci, Dept Mol Biol & Genet, Ceske Budejovice 37005, Czech Republic

[6] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA

[7] Albert Einstein Coll Med, Dept Neurol, 1300 Morris Pk Ave, Bronx, NY 10461 USA

[8] Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA

来源：

NUCLEIC ACIDS RESEARCH | 2024年 / 52卷 / 11期

基金：

荷兰研究理事会; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

H3K4; METHYLATION; IMPAIRED REMOVAL; FOLD CHANGE; FRAGILE-X; MUTATIONS; DYSFUNCTION; JARID1C; MODEL;

D O I：

10.1093/nar/gkae261

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genes encoding the KDM5 family of transcriptional regulators are disrupted in individuals with intellectual disability (ID). To understand the link between KDM5 and ID, we characterized five Drosophila strains harboring missense alleles analogous to those observed in patients. These alleles disrupted neuroanatomical development, cognition and other behaviors, and displayed a transcriptional signature characterized by the downregulation of many ribosomal protein genes. A similar transcriptional profile was observed in KDM5C knockout iPSC-induced human glutamatergic neurons, suggesting an evolutionarily conserved role for KDM5 proteins in regulating this class of gene. In Drosophila, reducing KDM5 changed neuronal ribosome composition, lowered the translation efficiency of mRNAs required for mitochondrial function, and altered mitochondrial metabolism. These data highlight the cellular consequences of altered KDM5-regulated transcriptional programs that could contribute to cognitive and behavioral phenotypes. Moreover, they suggest that KDM5 may be part of a broader network of proteins that influence cognition by regulating protein synthesis. Graphical Abstract

引用

页码：6201 / 6219

页数：19