Kelsey Group

Kelsey Group
Kelsey Group
Gavin Kelsey
Head of Programme
Kelsey Group

Research Summary

As well as genetic information, the egg and sperm also contribute epigenetic annotations that may influence gene activity after fertilisation. These annotations may be direct modifications of the DNA bases or of the proteins around which the DNA is wrapped into chromatin. Our goal is to understand whether, through epigenetics, factors such as a mother’s age or diet have consequences on the health of a child.
 
We examine how epigenetic states are set up in oocytes – or egg cells – and influence gene expression in the embryo. For example, repressive chromatin marks in oocytes lead to long-term silencing of genes inherited from the mother, particularly in cells that will form the placenta. We are also interested in how variations in DNA methylation come about in oocytes and whether we can use this variation as a marker for oocyte quality and embryo potential. To investigate these questions, we develop methods to profile epigenetic information in very small numbers of cells or even in single cells.

Latest Publications

Van de Pette M, Dimond A, Galvão AM, Millership SJ, To W, Prodani C, McNamara G, Bruno L, Sardini A, Webster Z, McGinty J, French PMW, Uren AG, Castillo-Fernandez J, Watkinson W, Ferguson-Smith AC, Merkenschlager M, John RM, Kelsey G, Fisher AG Epigenetics

Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. Similar processes in mammals can also affect phenotype through intergenerational or trans-generational mechanisms. Here we generate a luciferase knock-in reporter mouse for the imprinted Dlk1 locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternal Dlk1 in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneous Dlk1 mis-expression is seen exclusively among animals born to F1-exposed females. Oocytes from these females show altered gene and microRNA expression without changes in DNA methylation, and correct imprinting is restored in subsequent generations. Our results illustrate how diet impacts the foetal epigenome, disturbing canonical and non-canonical imprinting mechanisms to modulate the properties of successive generations of offspring.

+view abstract Nature communications, PMID: 35513363 05 May 2022

Rodríguez-Ubreva J, Arutyunyan A, Bonder MJ, Del Pino-Molina L, Clark SJ, de la Calle-Fabregat C, Garcia-Alonso L, Handfield LF, Ciudad L, Andrés-León E, Krueger F, Català-Moll F, Rodríguez-Cortez VC, Polanski K, Mamanova L, van Dongen S, Kiselev VY, Martínez-Saavedra MT, Heyn H, Martín J, Warnatz K, López-Granados E, Rodríguez-Gallego C, Stegle O, Kelsey G, Vento-Tormo R, Ballestar E Epigenetics

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.

+view abstract Nature communications, PMID: 35365635 01 Apr 2022

Hanna CW, Huang J, Belton C, Reinhardt S, Dahl A, Andrews S, Stewart AF, Kranz A, Kelsey G Epigenetics, Bioinformatics

Histone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 (KMT2B) are essential for oogenesis. We investigated changes in H3K4me3 in Setd1b conditional knockout (cKO) oocytes using ultra-low input ChIP-seq, with comparisons to DNA methylation and gene expression analyses. H3K4me3 was redistributed in Setd1b cKO oocytes showing losses at active gene promoters associated with downregulated gene expression. Remarkably, many regions also gained H3K4me3, in particular those that were DNA hypomethylated, transcriptionally inactive and CpG-rich, which are hallmarks of MLL2 targets. Consequently, loss of SETD1B disrupts the balance between MLL2 and de novo DNA methyltransferases in determining the epigenetic landscape during oogenesis. Our work reveals two distinct, complementary mechanisms of genomic targeting of H3K4me3 in oogenesis, with SETD1B linked to gene expression and MLL2 to CpG content.

+view abstract Nucleic acids research, PMID: 35137160 07 Feb 2022

Group Members

Gavin Kelsey

Head of Programme

Christian Belton

Postdoc Research Scientist

Laura Benson

Visiting Scientist

Antonio Galvao

Postdoc Research Scientist

Diljeet Gill

Visiting Scientist

Irene Hernando Herraez

Postdoc Research Scientist

Elena Ivanova

Postdoc Research Scientist

Carmen Jones

PhD Student

Oana Kubinyecz

PhD Student

Leah McHugh

PhD Student

Connor Roberts

Research Assistant

Marco Sciacovelli

Visiting Scientist

Carine Stapel

Marie Curie Fellow

Jasmin Stowers

Visiting Scientist

Brendan Terry

PhD Student

Christopher Todd

Visiting Scientist