title: Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes.
abstract: Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Leo
authors.initials: L
authors.lastname: Hata
authors.forename: Masao
authors.initials: M
authors.lastname: Murakami
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Masataka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D018507:Gene Expression Regulation, Developmental; D023061:Gene Order; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C096823:Zfp90 protein, mouse