Life Sciences Research for Lifelong Health

Gavin Kelsey

Research Summary

It is thought that epigenetic information can be programmed by environmental factors, such as diet and early life experiences, and such changes can be perpetuated long after these exposures and potentially to future generations.  Such epigenetic programming may contribute to our risk of developing disease in later life.  Imprinted genes (whose expression is determined by the parent that contributed them) are a model for how epigenetic events in gametes of one generation dictate gene activity in the next.

Our mapping of methylation of DNA in the egg, sperm and embryo suggests that this epigenetic influence may extend well beyond the small number of known imprinted genes.  Using genome-wide approaches, we are tracking the fate of DNA methylation patterns inherited from the egg and sperm, the stability of these marks throughout the lifetime and ageing, and how they affect activity of associated genes.  In particular, we are investigating whether DNA methylation in particular populations of neurons in the hypothalamus, the part of the brain that senses nutritional status to control metabolism and appetite, is altered by exposure to altered diets and may modify response to nutritional status.

The discovery that gene transcription is essential for DNA methylation and imprint establishment may help to explain how the methylation modifications in the genome of the egg may be modified by adverse environments or how imprinting is disrupted in some imprinted gene disorders.

Latest Publications

Cultured bovine embryo biopsy conserves methylation marks from original embryo.
Fonseca Balvís N, Garcia-Martinez S, Pérez-Cerezales S, Ivanova E, Gomez-Redondo I, Hamdi M, Rizos D, Coy P, Kelsey G, Gutierrez-Adan A

A major limitation of embryo epigenotyping by chromatin immunoprecipitation analysis is the reduced amount of sample available from an embryo biopsy. We developed an in vitro system to expand trophectoderm cells from an embryo biopsy to overcome this limitation. This work analyzes whether expanded trophectoderm (EX) is representative of the trophectoderm (TE) methylation or adaptation to culture has altered its epigenome. We took a small biopsy from the trophectoderm (30-40 cells) of in vitro produced bovine-hatched blastocysts and cultured it on fibronectin-treated plates until we obtained ∼4 × 104 cells. The rest of the embryo was allowed to recover its spherical shape and, subsequently, TE and inner cell mass were separated. We examined whether there were DNA methylation differences between TE and EX of three bovine embryos using whole-genome bisulfite sequencing. As a consequence of adaptation to culture, global methylation, including transposable elements, was higher in EX, with 5.3% of quantified regions showing significant methylation differences between TE and EX. Analysis of individual embryos indicated that TE methylation is more similar to its EX counterpart than to TE from other embryos. Interestingly, these similarly methylated regions are enriched in CpG islands, promoters and transcription units near genes involved in biological processes important for embryo development. Our results indicate that EX is representative of the embryo in terms of DNA methylation, thus providing an informative proxy for embryo epigenotyping.

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Biology of reproduction, 97, 1529-7268, 189-196, 2017

PMID: 29044423

Single-cell epigenomics: Recording the past and predicting the future.
Kelsey G, Stegle O, Reik W

Single-cell multi-omics has recently emerged as a powerful technology by which different layers of genomic output-and hence cell identity and function-can be recorded simultaneously. Integrating various components of the epigenome into multi-omics measurements allows for studying cellular heterogeneity at different time scales and for discovering new layers of molecular connectivity between the genome and its functional output. Measurements that are increasingly available range from those that identify transcription factor occupancy and initiation of transcription to long-lasting and heritable epigenetic marks such as DNA methylation. Together with techniques in which cell lineage is recorded, this multilayered information will provide insights into a cell's past history and its future potential. This will allow new levels of understanding of cell fate decisions, identity, and function in normal development, physiology, and disease.

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Science (New York, N.Y.), 358, 1095-9203, 69-75, 2017

PMID: 28983045

DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies).
Canovas S, Ross PJ, Kelsey G, Coy P

DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable. Indeed, as we also review here, studies showing the effect of culture media, ovarian stimulation or embryo transfer on the methylation pattern of embryos emphasize the need to face ART-associated defects and search for strategies to mitigate adverse effects on the health of ART-derived children.

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BioEssays : news and reviews in molecular, cellular and developmental biology, , 1521-1878, , 2017

PMID: 28940661

Group Members

Latest Publications

Cultured bovine embryo biopsy conserves methylation marks from original embryo.

Fonseca Balvís N, Garcia-Martinez S, Pérez-Cerezales S

Biology of reproduction
97 1529-7268:189-196 (2017)

PMID: 29044423

Single-cell epigenomics: Recording the past and predicting the future.

Kelsey G, Stegle O, Reik W

Science (New York, N.Y.)
358 1095-9203:69-75 (2017)

PMID: 28983045

DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies).

Canovas S, Ross PJ, Kelsey G

BioEssays : news and reviews in molecular, cellular and developmental biology
1521-1878: (2017)

PMID: 28940661

Genomic imprinting beyond DNA methylation: a role for maternal histones.

Hanna CW, Kelsey G

Genome biology
18 1474-760X:177 (2017)

PMID: 28927436

The histone 3 lysine 4 methyltransferase Setd1b is a maternal effect gene required for the oogenic gene expression program.

Brici D, Zhang Q, Reinhardt S

Development (Cambridge, England)
1477-9129: (2017)

PMID: 28619824

Transcription and chromatin determinants of de novo DNA methylation timing in oocytes.

Gahurova L, Tomizawa SI, Smallwood SA

Epigenetics & chromatin
10 1756-8935:25 (2017)

PMID: 28507606

Establishment and functions of DNA methylation in the germline.

Stewart KR, Veselovska L, Kelsey G

Epigenomics
1750-192X: (2016)

PMID: 27659720

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity.

Clark SJ, Lee HJ, Smallwood SA

Genome biology
17 1474-760X:72 (2016)

PMID: 27091476

Pervasive polymorphic imprinted methylation in the human placenta.

Hanna CW, Peñaherrera MS, Saadeh H

Genome research
1549-5469: (2016)

PMID: 26769960

Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity.

Angermueller C, Clark SJ, Lee HJ

Nature methods
1548-7105: (2016)

PMID: 26752769