Investigating the role of transcription factors in regulating trophectoderm specification during human embryogenesis

Primary Supervisor: Peter Rugg-Gunn (peter.rugg-gunn@babraham.ac.uk)

Second Supervisor: Kathy Niakan (kkn21@cam.ac.uk)

Host Department or Institute: Babraham Institute and Department of Physiology, Development and Neuroscience

Project description

The first lineage specification event in human embryogenesis generates two distinct cell populations: the inner cell mass and the outer trophectoderm layer. Trophectoderm cells are essential for embryo attachment to the endometrium and the initiation of implantation, and they subsequently give rise to the trophoblast compartment of the placenta.

Research from our laboratories and others has shown that many of the mechanisms controlling trophectoderm specification are conserved across mammals, including mouse and cow. However, human embryos display several distinctive features. These include a relatively late commitment to inner cell mass and trophectoderm lineages, differences in the expression and function of key regulatory factors, and altered developmental timing. These unique characteristics highlight the importance of studying lineage specification directly in human embryos and raise fundamental questions about how the first developmental decisions are regulated.

The aim of this PhD project is to define how transcription factors regulate trophectoderm specification during early human development. To achieve this, you will work jointly with the research groups of Peter Rugg-Gunn (Babraham Institute) and Kathy Niakan (Department of Physiology, Development and Neuroscience, University of Cambridge).

In the first phase of the project, you will use small-scale chromatin profiling methods developed in the Rugg-Gunn laboratory (Wang et al., 2025) to map the genomic binding sites of candidate transcription factors in trophectoderm cells from human preimplantation embryos. These experiments will reveal the genes and regulatory elements targeted by these factors and provide new insights into the co-factors and regulatory networks that control trophectoderm specification.

You will then extend these studies to early post-implantation trophoblast using recently established in vitro embryo implantation models (Mole et al., 2026). Comparing transcription factor occupancy across developmental stages will provide a detailed understanding of how regulatory networks change during trophoblast development. There may also be opportunities to compare these patterns with stem cell-derived embryo models, such as blastoids.

In the second phase of the project, you will employ state-of-the-art base-editing approaches developed by the Niakan laboratory (Bower et al., 2026) to investigate the cellular and molecular consequences of disrupting key transcription factors during human embryo development.

Together, these studies will provide exciting new insight into the mechanisms governing the first lineage decision in human embryogenesis and advance our understanding of how transcription factors establish and maintain trophectoderm identity.

You will be a member of the Rugg-Gunn laboratory within the Epigenetics Programme at the Babraham Institute and the Niakan laboratory at the University of Cambridge and work closely across the two sites. Full training will be provided in all techniques required for the project, including human embryo culture and handling, chromatin profiling, sequencing, bioinformatic analysis, and a wide range of molecular biology methods. The project is supported by outstanding facilities and expertise across both institutes.

Cambridge provides an exceptional environment for developmental and stem cell biology research. We are closely connected to this thriving community through the Loke Centre for Trophoblast Research, the Cambridge Stem Cell Institute, the Reproduction Strategic Research Initiative, and the Cambridge Epigenetics Club.

For more details of our research, please see:

http://www.babraham.ac.uk/our-research/epigenetics/peter-rugg-gunn 

https://www.trophoblast.cam.ac.uk/people/kathy-niakan 

Candidate background

The project will involve training and research experiments across both the Babraham Institute and Department of Physiology, Development and Neuroscience. An essential criteria is a willingness to travel across both sites for training and experimental work and an integration within both teams.

References

Bower OJ, R Orsi AE, McMahon R, Staneva D, Blagrove JR, Singh K, Simon CS, McCarthy A, Garcia P, Shaikly V, Taranissi M, Wilding M, Serhal P, Odia RA, Vasilic M, Choudhary M, Papathanasiou A, Elder K, Snell P, Christie L, Arbab M, Liu DR, Herbert M, Harasimov K, Niakan KK. Base editing reveals an essential role for NANOG in human embryogenesis. Nature. 2026. doi: 10.1038/s41586-026-10792-1.

Brumm AS, McCarthy A, Gerri C, Fallesen T, Woods L, McMahon R, Papathanasiou A, Elder K, Snell P, Christie L, Garcia P, Shaikly V, Taranissi M, Serhal P, Odia RA, Vasilic M, Osnato A, Rugg-Gunn PJ, Vallier L, Hill CS, Niakan KK. Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling. Developmental Cell. 2025. doi: 10.1016/j.devcel.2024.10.020.

Gerri C, McCarthy A, Alanis-Lobato G, Demtschenko A, Bruneau A, Loubersac S, Fogarty NME, Hampshire D, Elder K, Snell P, Christie L, David L, Van de Velde H, Fouladi-Nashta AA, Niakan KK. Initiation of a conserved trophectoderm program in human, cow and mouse embryos. Nature. 2020. doi:10.1038/s41586-020-2759-x.

Molè MA, Elderkin S, Zorzan I, Penfold C, Horsley N, Pokhilko A, Polanek M, Palomar A, Sinha M, Wang Y, Quiñonero A, Androulidakis C, Acton R, Balmanno K, Jarman A, Srinivasan J, Bendall A, Morales-Álvarez S, Yagüe-Serrano R, Heywood K, Harbottle S, Vasilic M, Cawood S, Seshadri S, Serhal P, Weavers L, Sarris I,Mania A, Gibbons R, Laurier L, Sánchez-Ribas I, Mercader A, Alamá P, Bui AH, Burton GJ, Cindrova-Davies T, Fernando RC, McCarthy A, Aghajanova L, Nel-Themaat L, Lathi RB, Cook SJ, Niakan KK, Dunn AR, Domínguez F, Rugg-Gunn PJ. Modeling human embryo implantation in vitro. Cell. 2026. doi:10.1016/j.cell.2025.10.027.

Wang Y, Li J, Malcolm AA, Mansfield W, Clark SJ, Argelaguet R, Biggins L, Acton RJ, Andrews S, Reik W, Kelsey G, Rugg-Gunn PJ. Combinatorial profiling of multiple histone modifications and transcriptome in single cells using scMTR-seq. Science Advances 2025. doi: 10.1126/sciadv.adu3308.