Contact
Biography
Helen Miranda Knight studied Natural Science as an undergraduate and did a MRes in Neuroscience at Edinburgh University working in the in the labs of Douglas Blackwood and Richard G Morris. She was subsequently involved with the writing of 'The Hippocampus Book'. She completed a PhD in Psychiatric Genetics at the Institute of Genetics and Cancer at Edinburgh. After holding a post-doctoral position under Trevor Robbins and Barbara Sahakian at the Behavioral and Clinical Neuroscience Institute (BCNI), Cambridge University, and MRC fellowship under Chris Ponting at the MRC Functional Genomics Unit (now part of the Department of Physiology, Anatomy and Genetics) Oxford University, in 2013 she came to Nottingham University in to start her own group. Her lab investigates genomic, epigenetic and epitranscriptomic processes contributing to neurodevelopmental, neurodegenerative and cognitive disorders.
She has been an elected member of the Senate since 2020 and a member of the UoN Knowledge Exchange Committee since 2021.
Dr Knight is a Genetic Society UoN Ambassador https://genetics.org.uk/
Expertise Summary
My expertise spans cognition, epidemiology, and molecular biology as well as molecular 'omics' technologies such a genomics, epigenetics, proteomics and transcriptomics. My focus has been on neurodevelopmental diseases such as schizophrenia, psychosis and autism, and neurodegenerative conditions such as specific forms of dementia, e.g. Lewy Body diseases.
My lab has used a number of molecular approaches including identifying rare variants and loss-of-function mutations in clinical populations to examine the molecular factors contribution to disease states. We have also interrogated large cohort datasets to investigate health and nutritional factors, and changes in cognition and disease phenotypes.
In recent years, my team has been investigating the newly emerging field of RNA modifications (epitranscriptomics), i.e. m6A and m5C modifications, and how these processes contribute to, and regulate, change in transcriptional outputs, synaptic and neuronal function, and brain disease neuropathology.
Teaching Summary
My teaching interests are in human genetics and epigenetics of brain and neurological disorders and molecular services in health care.
Undergraduate and postgraduate teaching
Bachelor of Medical Sciences(BMedSci)
MSc Molecular genetics and Diagnostics.
Convener for the following MSc Molecular genetics and Diagnostics modules.
MSc Molecular genetics and Diagnostics: Molecular Services in Health Care
MSc Molecular genetics and Diagnostics: Molecular Basis of Genetic Disorders
Research project supervision
Bachelor of Medical Sciences(BMedSci)
MSc Molecular genetics and Diagnostics
Student tutoring
Tutor for: MSc Molecular Genetics and Diagnostics; MSc Clinical Microbiology; UG BMedSc, course students.
Research Summary
My lab focuses on investigating the genetic and epigenetic basis of brain diseases and cognitive traits. We perform molecular techniques to investigate genomics, transcriptomic, and proteomic changes… read more
Selected Publications
FLITTON, MILES, RIELLY, NICHOLAS, WARMAN, RHIAN, WARDEN, DONALD, SMITH, A. DAVID, MACDONALD, IAN A. and KNIGHT, HELEN MIRANDA, 2019. Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline NEUROBIOLOGY OF AGING. 78, 64-73 KNIGHT, H.M., PICKARD, B.S., MACLEAN, A., MALLOY, M.P., SOARES, D.C., MCRAE, A.F., CONDIE, A., WHITE, A., HAWKINS, W., MCGHEE, K., VAN BECK, M., MACINTYRE, D.J., STARR, J.M., DEARY, I.J., VISSCHER, P.M., PORTEOUS, D.J., CANNON, R.E., ST CLAIR, D., MUIR ,W.J. and BLACKWOOD, D.H.R., 2009. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression American Journal of Human Genetics. 85(6), 833-846 PICKARD, B.S., KNIGHT, H.M., HAMILTON, R.S., SOARES, D.C., WALKER, R., BOYD, J.K.F., MACHELL, J., MACLEAN, A., MCGHEE, K.A., CONDIE, A., PORTEOUS, D.J., ST. CLAIR, D., DAVIS, I., BLACKWOOD, D.H.R. and MUIR, W.J., 2008. A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder Proceedings of the National Academy of Sciences. 105(39), 14940-14945
Current Research
My lab focuses on investigating the genetic and epigenetic basis of brain diseases and cognitive traits. We perform molecular techniques to investigate genomics, transcriptomic, and proteomic changes in disease. We use sequencing 'omics' techniques and large datasets, advanced microscopy (STEM, TEM, SRM, confocal), cell cultures and human brain tissue to examine how disease develops and progresses. The different strands of lab include:
- RNA epi-transcriptomics and brain function
We have demonstrated in vitro and in situ brain tissue that m6A modified RNAs are in pre- and post- synaptic sites. We have also shown that the m6A eraser, ALKBH5, is involved in active translation during synaptic plasticity; and that the YTHDF1 and YTHFDF3 readers exhibit differential roles during synaptic maturation. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles, but in both neuronal and glial cell-rich tissue, we found that m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades.
We are currently further characterising the role m6A RNA modification during synaptic plasticity. We are also investigating new roles for enzymes involved in RNA metabolism and how translation of non-conventional proteins,e.g. micro proteins, are regulated. To do this we are developing sequencing technologies and in collaboration with others, sequencing software.
Current lab members: Joseph Stones; Oliver Orji; Hala Shaker.
Past Lab members: Braulio Martinez De La Cruz; Eleanor Bellows, Maria Isabel Haig, Merve Demirbugen Öz.
Papers:
Martinez De La Cruz, B., Markus, R., Malla, S. et al. …Knight, HM., Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging. Mol Psychiatry 26, 7141-7153 (2021). https://doi.org/10.1038/s41380-021-01282-z
Baron F, Zhang M, Archer N, Bellows E, Knight HM, Welham S, Rutland CS, Mongan NP, Hayes CJ, Fray RG, Bodi Z. The importance of m6A topology in chicken embryo mRNA: a precise mapping of m6A at the conserved chicken β-actin zipcode. RNA. 2023 Jun;29(6):777-789. doi: 10.1261/rna.079615.123.
Review 2024:
Bellows, E., Fray, R.G., Knight, H.M., and Archer, N. (2024). The expanding role of cap-adjacent modifications in animals. Frontiers in RNA Research 2. 10.3389/frnar.2024.1485307.
2. RNA epi-transcriptomics and brain disease
We have discovered that the abundance of different forms of RNA methylation and effector proteins are disrupted in neurodegenerative diseases and that in some diseases, such a Dementia with Lewy body, there is a significant increase in m6A-RNAs whereas in other diseases there is significant reduction in modified-RNAs and location of modified RNAs within neuronal cells, e.g. Parkinson's disease and Mild Cognitive Impairment. This suggests that although there may be similar pathological features across diseases, e.g., alpha synuclein aggregates known a Lewis bodies, disruption to RNA metabolism processes which maybe a driver, differs between the diseases.
m5C RNA effector proteins are differentially expressed in Alzheimer's Disease and Traumatic brain Injury.
m6A-modified RNA is significantly more abundant in Lewy body dementia and significantly reduced and misplaced brain cells in Parkinson's Disease (PD) and Mild Cognitive Impairment (MCI). m6A RNA reader and anti-reader effector protein abundance are significantly changed in DLB, PD and MCI and Alzheimer's Disease.
Lab members: Adriana Perez Grovas-Saltijeral, Hala Shaker, Lauryn Walker, Masar Radhi.
Past Lab members: Braulio Martinez De La Cruz; Merve Demirbugen Öz, Eleanor Bellows, Maria Isabel Haig.
Papers:
Martinez De La Cruz, B., …Knight, H.M., "m6A mRNA methylation in human brain is disrupted in Lewy body disorders", Neuropathol Appl Neurobiol. 2023; 49(1).
Perez Grovas-Saltijeral, A., …Knight, H.M., 'Differential Expression of m5C RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer's disease and Traumatic Brain Injury', Mol Neurobiol. 2023 Apr;60(4):2223-2235.
Knight,H. M., Demirbugen Öz. M., PerezGrovas-Saltijeral, A.,. Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders. Neural Regeneration Research :10.4103/1673-5374.385858.
Orji OC, Stones J, Rajani S, Markus R, Öz MD, Knight HM. Global Co-regulatory Cross Talk Between m6A and m5C RNA Methylation Systems Coordinate Cellular Responses and Brain Disease Pathways. Mol Neurobiol. 2024 Nov 5. doi: 10.1007/s12035-024-04555-0.
- Biomarkers for early Alzheimer's disease, Dementia with Lewy Bodies (DLB), cognitive decline and psychosis
Current Lab members: Gamze Gizem Tekeli, Fatma Busra Isik
Papers:
Isik FB, Knight HM, Rajkumar AP. Extracellular vesicle microRNA-mediated transcriptional regulation may contribute to dementia with Lewy bodies molecular pathology. Acta Neuropsychiatr. 2023 Jun 21:1-10. doi: 10.1017/neu.2023.27.
Past Research
1. Rare coding variants and genetic architecture of complex disease
ABCA13 ATP-binding cassette sub-family A member 13
A patient with schizophrenia was found to have a chromosomal abnormality which directly disrupted one gene, ABCA13, a lipid membrane transporter protein. Through exon sequencing of the functional domains of ABCA13, multiple rare coding variants were identified. Follow-up pedigree and case-control association studies strongly suggest that mutations within this gene, significantly contribute to the genetic aetiology of schizophrenia, bipolar disorder and major depression. This work raises key questions into the type of mutations underlying complex disease, for example; the frequency of rare risk variants (private to a family, ultra-rare, or 1-2%), whether carrying 2 or more rare coding variants (compound heterozygotes) is a feature of risk burden, and how common it is to have variants that contribute to several disorders which cross diagnostic categories. ABCA13 is now known to be involved in vesicle cholesterol accumulation and synaptic vesicle endocytosis and has been confirmed as a genetic risk gene for psychiatric disorders.
ABCA13 cytogenetic lesion and rare coding variants in families with Schizophrenia, bipolar disorder and major depression
Knight, H.M., Pickard, B.S., et al.,…Blackwood, D.H (2009) "A cytogenetic abnormality and rare coding variants identify a transporter as a candidate gene for schizophrenia, bipolar disorder and depression". The American Journal of Human Genetics, 85:1-14.
2. Glutamatergic neurotransmitter genes and risk for neurodevelopmental disorders
GRIK4/GLUK4 glutamate ionotropic kainite receptor 4 subunit
A deletion within the 3' untranslated region of the GRIK4 gene was identified as a protective factor for bipolar disorder. RNA secondary structure analysis in conjunction with evidence of increased relative mRNA abundance of the protective deletion allele suggested that this common variant may have a functional impact through differential mRNA stability. Using immunohistochemistry, GLUK4 protein expression was characterized in key regions of human brain and a genotype/protein expression correlation study indicated that GLUK4 expression was significantly increased in subjects carrying the protective allele. The protective deletion allele is also associated with better cognitive performance.
A 'protective' deletion within GRIK4/GLUK4 is increased in the hippocampus and cortex and associated with higher cognitive performance.
Past Lab members: Maria Koromina, Miles Flitton.
Papers:
Koromina, M., Flitton. M., UK10K., Mellor, I., Knight, H.M. (2019) "A Kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort". World Journal of Biological Psychiatry, 20(5):393-401.
Koromina. M., Flitton. M., Blockley. A., Mellor. I.R., Knight, H.M. (2019) "Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities". Sci Rep.16;9 (1):19215.
Knight HM, Walker R, James R, Blackwood DH, Muir WJ, Pickard BS. (2012) GRIK4/KA1 protein expression in human brain tissue and correlation with a genetic variant associated with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 159B(1):21-9.
Pickard BS, Knight HM, Hamilton RS, Soares DC, Walker R, Boyd JK, Machell J, Maclean A, McGhee KA, Condie A, Porteous DJ, St Clair D, Davis I, Blackwood DH, Muir WJ (2008) A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. PNAS 105:14940-14945.
3. Functional Genomics, DNA methylation and methionine metabolism factors
Disease risk alleles and non-coding functional effects.
Genome-wide array case-control association studies and population/pedigree next generation re-sequencing studies frequently give rise to results implicating regions or variants which are not in coding regions of genes but are potentially associated/linked with a trait or disease. How do we interpret these non-coding signals? And how do we tell if common variants are directly contributing to a phenotype or are merely associated through being near a causative variant (synthetic association)? One method currently used is to examine whether the variants are located within or/and directly disrupt regulatory element and thus could have a functional non-coding effect. This involves bioinformatic data mining of cohort and functional genomic datasets for regulatory features such as different species of non-coding RNAs, DNA and RNA methylation, as well as functional studies.
Cognitive change correlates with methionine metabolism factors and DNMT3L genotype.
Past lab members: Nicholas Rielly, Miles Flitton.
Papers:
Flitton, M., Rielly, N., Warman, R., Warden, D., Smith, A D., Macdonald, I.A., Knight, H.M. (2019) "Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline". Neurobiol Aging. Jun;78:64-73.
Flitton. M., Macdonald, I.A., Knight, H.M. (2019) "Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals". Nutritional Neuroscience, 22(6):401-408. Epub 2017.
Davies,G., Harris, S.E., Reynolds, C.H., Payton, A., Knight, H.M., Liewald, D.C., et al., (2014) A Genome-Wide Association Study implicates the APOE/TOMM40 locus in non-pathological cognitive ageing. Molecular Psychiatry, 19(1):76-87.