Topic
RFX4
About: RFX4 is a research topic. Over the lifetime, 10 publications have been published within this topic receiving 274 citations. The topic is also known as: NYD-SP10 & regulatory factor X4.
Papers
TL;DR: A comprehensive analysis of all the eight human RFX genes (RFX1–8), their spatial and temporal expression profiles, potential upstream regulators and target genes, and a new grouping of the RFX family based on protein domain composition are provided.
Abstract: Evolutionarily conserved RFX transcription factors (TFs) regulate their target genes through a DNA sequence motif called the X-box. Thereby they regulate cellular specialization and terminal differentiation. Here, we provide a comprehensive analysis of all the eight human RFX genes (RFX1–8), their spatial and temporal expression profiles, potential upstream regulators and target genes. We extracted all known human RFX1–8 gene expression profiles from the FANTOM5 database derived from transcription start site (TSS) activity as captured by Cap Analysis of Gene Expression (CAGE) technology. RFX genes are broadly (RFX1–3, RFX5, RFX7) and specifically (RFX4, RFX6) expressed in different cell types, with high expression in four organ systems: immune system, gastrointestinal tract, reproductive system and nervous system. Tissue type specific expression profiles link defined RFX family members with the target gene batteries they regulate. We experimentally confirmed novel TSS locations and characterized the previously undescribed RFX8 to be lowly expressed. RFX tissue and cell type specificity arises mainly from differences in TSS architecture. RFX transcript isoforms lacking a DNA binding domain (DBD) open up new possibilities for combinatorial target gene regulation. Our results favor a new grouping of the RFX family based on protein domain composition. We uncovered and experimentally confirmed the TFs SP2 and ESR1 as upstream regulators of specific RFX genes. Using TF binding profiles from the JASPAR database, we determined relevant patterns of X-box motif positioning with respect to gene TSS locations of human RFX target genes. The wealth of data we provide will serve as the basis for precisely determining the roles RFX TFs play in human development and disease.
88 citations
TL;DR: Results indicate that RFX4 is the first mammalian member of RFX family without transcriptional activation capacity and might function through selective interactions with other RFX members in transcriptional regulation.
60 citations
TL;DR: Regulatory factor X4 variant transcript 3 (RFX4_v3) gene disruption in mice demonstrated that interruption of a single allele prevented formation of the subcommissural organ, resulting in congenital hydrocephalus, while interruption of two alleles caused fatal failure of dorsal midline brain structure formation, suggesting that RFX4-v3 may act upstream of critical signaling pathways in the process of brain development.
Abstract: Regulatory factor X4 variant transcript 3 (Rfx4_v3) gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ, resulting in congenital hydrocephalus, while interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. To identify potential target genes for RFX4_v3, we used microarray analysis to identify differentially expressed genes in Rfx4_v3-deficient mouse brains at embryonic day 10.5, before gross structural changes were apparent. Of 109 differentially expressed transcripts, 24 were chosen for validation and 22 were confirmed by real-time PCR. Many validated genes encoded critical proteins involved in brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein (BMP) and retinoic acid (RA) pathways. Cx3cl1, a CX3C-type chemokine gene that is highly expressed in brain, was down-regulated in the Rfx4_v3-null mice. Both human and mouse Cx3cl1 proximal promoters contained highly conserved X-boxes, known cis-acting elements for RFX protein binding. Using the Cx3cl1 promoter as an example of a target gene, we demonstrated direct binding of RFX4_v3 to the Cx3cl1 promoter, and trans-acting activity of RFX4_v3 protein to stimulate gene expression. These data suggest that RFX4_v3 may act upstream of critical signaling pathways in the process of brain development.
44 citations
TL;DR: The findings indicate the potential functional relevance of the associated haplotypes in RFX4 and now require replication in independent samples.
Abstract: The gene encoding the transcription factor RFX4 represents an excellent neurobiological and positional candidate gene for Bipolar disorder due to the potential involvement of RFX4 proteins in the regulation of circadian rhythms and the proximity of the locus to numerous linkage signals on chromosome 12q23. In this study we have sought to identify common variants within the gene, which might confer risk to the disease in our large UK Caucasian sample of Bipolar patients (676 DSMIV Bipolar I probands, 690 controls). RFX4 was screened for sequence variants and the LD block structure across the genomic region determined using 22 biallelic polymorphisms (minor allele frequency 0.1). Through analysis of 10 haplotype-tagging markers and using a two-stage approach (subset I: 347 cases, 374 controls; subset II: 329 cases, 316 controls), we identified a haplotype at rs10778502 and ss24735177, which showed nominally significant disease association in our full sample (haplotype-specific P=0.002, global P=0.017; subset I: haplotype-specific P=0.0002, global P=0.0008; subset II: haplotype-specific P=0.572, global P=0.109). Evidence for potential disease association with mutations across the RFX4 region came also from the analysis of the nearby microsatellite D12S2072 (empirical P=0.009 in our full sample). Investigation of RFX4 brain cDNA tagged by rs10778502 provided evidence for significant allelic differences in expression (P<0.001), where some of the variance was accounted for by the genotype at ss24735177. Our findings thus indicate the potential functional relevance of the associated haplotype and now require replication in independent samples.
31 citations
TL;DR: Comparisons of transcripts and protein levels for the regulatory factor X (RFX) family in cell populations from the three major phases of spermatogenesis imply that RFX2 is the most likely X box binding factor to influence novel gene expression during meiosis, that R FX1-3 may all play roles in haploid cells but that Rfx4 is much less prevalent than implied by its high transcript levels.
25 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2018 | 2 |
| 2014 | 1 |
| 2009 | 1 |
| 2008 | 2 |
| 2007 | 1 |
| 2006 | 1 |