Life Sciences Research for Lifelong Health

Stefan Schoenfelder

Dr Schoenfelder holds a Babraham Institute Career Progression Fellowship which provides two years of support for his research.

Research Summary

Functional organisation of the genome in 3D
98% of the DNA in our body is non-coding, i.e. does not carry the information needed to build proteins. Non-coding has sometimes been equated with ‘non-functional’, or called ‘junk’ in the past; today we know that this is far from the truth. Scattered throughout non-coding DNA is a plethora of so-called regulatory elements, including enhancers, silencers and insulators. These regulatory elements function like molecular switches to control which genes are active (and thus produce proteins) in which cells. This process of gene expression control is vital to allow cells – which all contain the same genes – to specialise to carry out different tasks, and to help them respond to changes.

Enhancers are a type of regulatory element that control gene expression over long distances. They contact their target genes via chromosomal interactions, often bridging large distances in the genome, with the intervening DNA ‘looping out’. To understand how enhancers work, we study them in the context of the three-dimensional organisation of the genome.
 
Our aim is to find regulatory elements and to understand which genes they control. We also aim to uncover the molecular mechanisms by which regulatory elements find their target genes in the three-dimensional space of the cell nucleus, and to understand how altering the function of regulatory elements can lead to developmental malformations and disease.
 
We study these questions in pluripotent stem cells – cells that have the potential to create all cell types in the adult body. We use a combination of molecular, genetic, biochemical and imaging approaches to study pluripotent stem cells in their ‘ground state’, and when they start to form new cell types – a process called cell lineage specification.
 
Techniques and Methods

Through high-resolution mapping and experimental perturbation of the spatial genome architecture, we aim to reveal gene regulatory principles that underpin cell states and cell fate transitions. This may ultimately pave the way for us to experimentally engineer 3D genome folding to achieve predictable outcomes on gene expression and cell fate choice, with potential implications for gene therapy and regenerative medicine.
 

Latest Publications

Long-range enhancer-promoter contacts in gene expression control.
Schoenfelder S, Fraser P

Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer-promoter contacts and their functional dissection. In this Review, we discuss novel concepts on how enhancer-promoter interactions are established and maintained, how the 3D architecture of mammalian genomes both facilitates and constrains enhancer-promoter contacts, and the role they play in gene expression control during normal development and disease.

+ View Abstract

Nature reviews. Genetics, , 1471-0064, , 2019

PMID: 31086298

Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages.
Schoenfelder S, Mifsud B, Senner CE, Todd CD, Chrysanthou S, Darbo E, Hemberger M, Branco MR

The establishment of the embryonic and trophoblast lineages is a developmental decision underpinned by dramatic differences in the epigenetic landscape of the two compartments. However, it remains unknown how epigenetic information and transcription factor networks map to the 3D arrangement of the genome, which in turn may mediate transcriptional divergence between the two cell lineages. Here, we perform promoter capture Hi-C experiments in mouse trophoblast (TSC) and embryonic (ESC) stem cells to understand how chromatin conformation relates to cell-specific transcriptional programmes. We find that key TSC genes that are kept repressed in ESCs exhibit interactions between H3K27me3-marked regions in ESCs that depend on Polycomb repressive complex 1. Interactions that are prominent in TSCs are enriched for enhancer-gene contacts involving key TSC transcription factors, as well as TET1, which helps to maintain the expression of TSC-relevant genes. Our work shows that the first developmental cell fate decision results in distinct chromatin conformation patterns establishing lineage-specific contexts involving both repressive and active interactions.

+ View Abstract

Nature communications, 9, 2041-1723, 4189, 2018

PMID: 30305613

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.
Koohy H, Bolland DJ, Matheson LS, Schoenfelder S, Stellato C, Dimond A, Várnai C, Chovanec P, Chessa T, Denizot J, Manzano Garcia R, Wingett SW, Freire-Pritchett P, Nagano T, Hawkins P, Stephens L, Elderkin S, Spivakov M, Fraser P, Corcoran AE, Varga-Weisz PD

Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice.

+ View Abstract

Genome biology, 19, 1474-760X, 126, 2018

PMID: 30180872

 

Group Members

Latest Publications

Long-range enhancer-promoter contacts in gene expression control.

Schoenfelder S, Fraser P

Nature reviews. Genetics
1471-0064: (2019)

PMID: 31086298

Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages.

Schoenfelder S, Mifsud B, Senner CE

Nature communications
9 2041-1723:4189 (2018)

PMID: 30305613

Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions.

Schoenfelder S, Javierre BM, Furlan-Magaril M

Journal of visualized experiments : JoVE
1940-087X: (2018)

PMID: 30010637

GOTHiC, a probabilistic model to resolve complex biases and to identify real interactions in Hi-C data.

Mifsud B, Martincorena I, Darbo E

PloS one
12 1932-6203:e0174744 (2017)

PMID: 28379994

Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

Freire-Pritchett P, Schoenfelder S, Várnai C

eLife
6 2050-084X: (2017)

PMID: 28332981

Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C.

Martin P, McGovern A, Massey J

PloS one
11 1932-6203:e0166923 (2016)

PMID: 27861577

Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.

McGovern A, Schoenfelder S, Martin P

Genome biology
17 1474-760X:212 (2016)

PMID: 27799070