Biomedical subjects

Ian R Jones

Publications and source records attributed to Ian R Jones.

8 recordsLinked to original sources

PubMed2026

3D epigenome of glial cell types in developing human cortex.

The human cortex is complex and heterogeneous, undergoing extensive expansion during development1,2. Our prior study of neurogenesis, including radial glia (RG), intermediate progenitor cells, excitatory neurons and interneurons demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding light on how non-coding genetic variants contribute to neuropsychiatric disorders by means of cell-type-specific gene regulation3. RG have a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular RG (vRG) and outer RG (oRG)4,5. Given their significance in cortical development, we conducted a comprehensive three-dimensional (3D) epigenomic analysis of four main glial populations, including vRG, oRG, oligodendrocyte precursor cells and microglia, from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation and 3D chromatin interactions, we identified cell-type-specific candidate cis-regulatory elements (cCREs) and validated their regulatory function using transgenic mouse embryos. Using machine learning, we prioritized 112 schizophrenia risk variants within glia cCREs and further confirmed the predicted vRG enhancer disruption by the rs4449074 risk allele in vivo. Finally, oRG cCREs are enriched for human accelerated regions compared with other cCREs and a subset of human accelerated regions show activity differences from their chimpanzee orthologues that interact with genes involved in neuronal development. Our findings advance the understanding of human-specific gene regulation during corticogenesis.

Journal Article↗

PubMed2024

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Animals↗

PubMed2005

Structural variants in the retinoid receptor genes in patients with schizophrenia and other psychiatric diseases.

Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20-24 patients with bipolar disorder (BPD), attention-deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARbeta, RARgamma, and RXRgamma genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia.

Alcoholism↗

PubMed2005

Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases.

Intriguing parallels have been noted previously between the biology of Vitamin D and the epidemiology of schizophrenia. We have scanned the Vitamin D receptor (VDR) gene by DOVAM-S (Detection of Virtually All Mutations-SSCP), a robotically enhanced multiplexed scanning method. In total, 100 patients with schizophrenia (86 Caucasians and 14 African-Americans) were scanned. In addition, pilot experiments were performed in patients with bipolar disorder (BPD) (24), autism (24), attention deficit hyperactivity disorder (ADHD) (24), and alcoholism (20). A total of 762 kb of the VDR genomic sequence was scanned. R208N and V339I were each found in one African-American patient, while absent in 35 African-American controls without schizophrenia (2/14 versus 0/35, P=0.08). Within the power of the study (> or =1.6-fold relative risk), the common M1T variant is not associated with schizophrenia. In the 92 scanned patients with other psychiatric diseases, R173S was found in a single patient with bipolar disorder. In conclusion, we describe three novel structural variants of the Vitamin D receptor. Further study is required to clarify their role, if any, in psychiatric disease.

Amino Acid Sequence↗

PubMed2004

MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism.

Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study.

3' Untranslated Regions↗

PubMed2004

Mutation scanning of the androgen receptor gene in patients with psychiatric disorders reveals highly conserved variants in alcoholic and phobia patients.

Sex steroids exert potent effects on mood and mental state in humans. They may contribute to the risk of psychiatric disorders. To investigate this hypothesis, coding and splice junction sequences of the androgen receptor gene were scanned in genomic DNA samples to search for variants affecting protein structure and expression (VAPSEs). Ninety-six schizophrenics, along with pilot samples of patients with bipolar disorder, attention-deficit hyperactivity disorder, alcoholism and autism were analyzed with DOVAM-S, a robotically enhanced, optimized form of single-strand conformation polymorphism analysis. A total of 669 kb of genomic sequence was analyzed. Two VAPSEs were identified: R726L was found in one of 17 scanned alcoholics, and P516S, a novel VAPSE, was identified in one of three phobia patients. There were no length trends of the CAG triplets associated with schizophrenia. R726L and P516S occur at highly conserved amino acids. Further study is required to assess whether these VAPSEs contribute to the risk of alcoholism or phobia or other diseases.

Alcoholism↗

PubMed2004

Peliosis of the spleen with massive recurrent haemorrhagic ascites, despite splenectomy, and associated with elevated levels of vascular endothelial growth factor.

We present the case of a 33-year-old man with isolated splenic peliosis, a rare pathological condition characterized by blood filled cystic lesions. The patient presented with recurrent massive haemorrhagic ascites, which did not resolve, despite a splenectomy. He was found to have massively elevated levels of vascular endothelial growth factor (VEGF). The clinical course of the disease was prolonged. Repeated blood transfusions for recurrent anaemia were required, in addition to repeated aspiration of reaccumulating haemorrhagic ascites and pleural effusion. The clinical course was not in keeping with previously reported cases. We have described an atypical clinical presentation in a patient with isolated splenic peliosis associated with elevated VEGF concentrations. No previously known associations for the condition were found despite thorough investigations. Management of the patient has been symptomatic and palliative. We have reviewed the various reported associations of peliosis and discussed the possible role of VEGF in this patient's condition.

Adult↗

PubMed2002

Management of amiodarone-induced thyrotoxicosis.

Thyrotoxicosis occurs in up to 3% of people prescribed amiodarone in the UK. The management of amiodarone-induced thyrotoxicosis remains a clinical challenge, as data on optimal treatment from controlled trials are not available. This review will focus on current lines of management.

Amiodarone↗