Long-Range Control of Gene Expression: Emerging Mechanisms and Disruption in Disease

Kleinjan, Dirk A.; Heyningen, Veronica van

doi:10.1086/426833

Cited by 781 publications

(664 citation statements)

References 168 publications

(207 reference statements)

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“…However, alteration of LMO7 expression is unlikely to cause the observed phenotypes: the breakpoint was 3¢ of this gene, whereas long-range position effects are generally associated with breakpoints in 5¢ regulatory regions. 27 Also, roughly equal expression of both LMO7 alleles was observed in the proband's lymphoblasts. BNC2 also showed biallelic expression in the proband's lymphoblasts, as judged by RT-PCR and DNA sequencing.…”

Section: Discussionmentioning

confidence: 90%

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development

et al. 2011

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We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9-and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was B400 kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein. The BNC2/Bnc2 gene is abundantly expressed in developing mouse and human periurethral tissues. In all, 6 of 48 unrelated subjects with distal hypospadias had nine novel nonsynonymous substitutions in BNC2, five of which were computationally predicted to be deleterious. In comparison, two of 23 controls with normal penile urethra morphology, each had a novel nonsynonymous substitution in BNC2, one of which was predicted to be deleterious. Bnc2 À/À mice of both sexes displayed a high frequency of distal urethral defects; heterozygotes showed similar defects with reduced penetrance. The association of BNC2 disruption with distal urethral defects and the gene's expression pattern indicate that it functions in urethral development.

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Section: Discussionmentioning

confidence: 90%

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development

et al. 2011

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“…Having said this, recent studies are suggesting the potential effect of intronic sequences. 24 If, however, the association of ADHD with rs1843809 of TPH2 is confirmed, it may represent LD with another variant that predisposes to ADHD. This presumptive causative variant would likely be located in the control or the coding regions of the gene.…”

Section: Discussionmentioning

confidence: 99%

Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD

et al. 2005

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Genetic and pharmacological studies have emphasised the role of serotonin 5-hydroxytryptamine (5-HT) as a possible etiologic factor in the development of attention-deficit hyperactivity disorder (ADHD). Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin from tryptophan. Originally, the TPH gene was thought to be widely expressed, but a second form of TPH, TPH2, was recently identified and the TPH2 gene was found to be solely expressed in the brain. We examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families. Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder (v 2 ¼ 12.2, P ¼ 0.0006, OR ¼ 2.36). Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered (OR ¼ 3.7). In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD. Further confirmation, preferably from different ethnic groups, is required to firmly implicate TPH2 in the pathophysiology of ADHD. Molecular Psychiatry ( Keywords: attention-deficit hyperactivity disorder (ADHD); tryptophan hydroxylase (TPH2); transmission disequilibrium test (TDT); serotonergic system, genetic association Attention-deficit hyperactivity disorder (ADHD) is a common neurological disorder affecting 3-6% of children worldwide. 1 It is one of the most common causes of referrals in family practice, paediatric neurology and child psychiatry. 2 Children can be diagnosed with ADHD as early as 5 years of age with males being more affected than females (ratio ranging from 3 : 1-9 : 1). Major symptoms of ADHD include inability to sustain attention, hyperactivity, impulsivity and aggressive behaviour. The consequences are devastating for family and peer relations as well as academic life. Behaviour at home and at school is disrupted and ADHD children have poor school performance compared to healthy and age-matched children. 1 Symptoms persist into adulthood in at least 30% of cases. The disorder is clinically heterogeneous and its aetiology remains unknown. However, several lines of evidence have implicated genetic and environmental factors as predisposing to the disorder. Heritability of ADHD is estimated to be between 70 and 90%. 3,4 Environmental factors such as low birth weight, delivery complications, alcohol consumption and smoking during pregnancy, environmental toxins and diet are all implicated. 5 Serotonin 5-hydroxytryptamine (5-HT) is a neurotransmitter involved in a variety of functions such as attention, sleep, memory and learning, locomotion, control of appetite, anxiety and drug abuse. 6 Reduction in serotonergic function has been linked to ADHD symptoms such as aggression and impulsivity. 6,7 In addition, recent pharmacological evidence supports the potential involvement of serotonergic syste...

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“…Strikingly, 50% of these SNPS are not located near genes and in fact, the strongest SNP at rs13194053 (P ¼ 9.54 Â 10 À9 ) is more than 29 kb away from its nearest gene HIST1H2AH. A functional role for many intergenic regions would not be surprising as many intergenic regions alter expression of upstream and downstream genes (Kleinjan and van Heyningen, 2005), and the mechanistic work-up of these SNPs will certainly require application of chromosome conformation capture and related technologies.…”

Section: Epigenome Organization and Higher Order Chromatin Structuresmentioning

confidence: 99%

Epigenetics in the Human Brain

Houston

Peter

Mitchell

et al. 2012

Neuropsychopharmacol

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Many cellular constituents in the human brain permanently exit from the cell cycle during pre-or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Here, we summarize the current knowledge base as it pertains to genome organization in the human brain, including the regulation of DNA cytosine methylation and hydroxymethylation, and a subset of (altogether 4100) residue-specific histone modifications associated with gene expression, and silencing and various other functional chromatin states. We propose that high-resolution mapping of epigenetic markings in postmortem brain tissue or neural cultures derived from induced pluripotent cells (iPS), in conjunction with transcriptome profiling and whole-genome sequencing, will increasingly be used to define the molecular pathology of specific cases diagnosed with depression, schizophrenia, autism, or other major psychiatric disease. We predict that these highly integrative explorations of genome organization and function will provide an important alternative to conventional approaches in human brain studies, which mainly are aimed at uncovering group effects by diagnosis but generally face limitations because of cohort size.

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Long-Range Control of Gene Expression: Emerging Mechanisms and Disruption in Disease

Cited by 781 publications

References 168 publications

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development

Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD

Epigenetics in the Human Brain

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