Julian Knight Group

Research Overview

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to disease. However fine mapping disease associations and resolving specific functionally important variants has proved problematic, particularly in non-coding DNA where variation may alter the way genes are regulated. This is a major bottleneck in current genetic research.

The overall aim of our research is to understand how genetic variation between individuals modulates genes critical to mounting an appropriate immune and inflammatory response, and so contributes to susceptibility to infectious and autoimmune diseases. A major focus of our work involves genes in the major histocompatibility complex (MHC) on chromosome 6p21, a remarkably polymorphic region strongly associated with susceptibility to autoimmune, infectious and other diseases but the causal functionally important variants remain largely unknown.

We adopt a number of different experimental approaches to defining regulatory genetic variants including analysis of allele-specific gene expression, expression quantitative trait mapping and detailed characterisation of how sequence diversity modulates the epigenetic and genetic control of gene expression. We study both human cell lines as a model system, and primary cells from healthy volunteers and patients with specific disease phenotypes including autoimmune disease, severe sepsis and primary immunodeficiencies to allow the context specificity of the effects of functionally important genetic variation to be resolved.

Podcast 'Genetic Variation in Inflammation and Immunity'

Publications

Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, and Knight JC. 2012 Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles. Nature Genetics 44, 502-510 View in PubMed

Vandiedonck C, Taylor MS, Lockstone H, Plant K, Taylor JM, Durrant C, Brockholme J, Fairfax BP, Knight JC. 2011 Pervasive haplotypic variation in the spliceo-transcriptome of the human Major Histocompatibility Complex. Genome Research 21, 1042 View in PubMed

Wicks K and Knight JC. 2011 Transcriptional repression and DNA looping associated with a novel regulatory element in the final exon of the lymphotoxin beta gene. Genes and Immunity 12, 126-135 View in PubMed

Fairfax P, Davenport E, Makino S, Hill AVS, Vannberg FO, Knight JC. 2011 A common haplotype of the tumour necrosis factor receptor 2 gene modulates endotoxin tolerance. Journal of Immunology 186, 3058-3065 View in PubMed

Maugeri N, Radhakrishnan J, Knight JC. 2010 Genetic determinants of HSP70 gene expression following heat shock. Human Molecular Genetics 19,4939-4947 View in PubMed

Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Handunnetthi L, Orton S, Handel AE, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. 2010 A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Research 20, 1352-1360 View in PubMed

Fairfax BP, Vannberg F, Radhakrishnan J, Hakonarson H, Keating BJ, Hill AVS, Knight JC. 2010 An integrated expression phenotype mapping approach defines common variants in LEP, ALOX15 and CAPNS1 associated with induction of IL-6. Human Molecular Genetics 19, 720-730 View in PubMed

Handunnetthi L, Ramagopalan SV, Ebers GC, Knight JC. 2010 Regulation of major histocompatibility complex class II gene expression, genetic variation and disease. Genes and Immunity 11, 99-112 View in PubMed

Knight JC. 2009. Human Genetic Diversity. Functional Consequences for Health and Disease. Oxford, Oxford University Press. Link

Ramagopalan SV, Maugeri NJ, Lincoln MR, Orton S, Dyment DA, DeLuca GC, Herrera BM, Handunnetthi L, Chao MJ, Sadovnick AD, Ebers GC, Knight JC. 2009 Expression of the Multiple Sclerosis associated MHC class II allele HLA-DRB1*1501 is Regulated by Vitamin D. PLoS Genetics 5 e1000369 View on PubMed

Taylor JM, Wicks K, Vandiedonck C, Knight JC. 2008 Chromatin profiling across the tumour necrosis factor gene locus reveals a complex, cell-type specific landscape with novel regulatory elements. Nucleic Acids Research 36, 4845-62 View on PubMed

Funding Sources

The Wellcome Trust, Medical Research Council, European Research Council, Crohn's and Colitis UK, Oxford Biomedical Research Centre

Research Area

Immunity and Inflammation

Keywords