Epigenetic mechanisms linking maternal choline supply and one-carbon metabolism during early perinatal development

Primary Supervisor: Geula Hanin (ghl35@cam.ac.uk)

Second Supervisor: Erica Watson (edw23@cam.ac.uk)

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

Project description

Early life nutrition has a profound influence on lifelong health, yet, the biological mechanisms linking maternal metabolism to offspring development remain poorly understood. The DOHaD (Developmental Origins of Health and Disease) paradigm establishes that environmental exposures during sensitive developmental windows shape metabolic and physiological trajectories across a lifespan. Most DOHaD studies focus on pregnancy and in utero life, which is largely dependent upon the placenta. However, the lactation period remains understudied in this context, even though it represents a second critical developmental window when maternal physiology shapes offspring growth through the milk. 

This project will investigate how maternal one-carbon metabolism regulates the nutritional and molecular signals delivered to the offspring before and after birth, with a particular focus on the essential nutrient choline. Population studies indicate that choline dietary intake is frequently suboptimal among pregnant women in high-income countries, and standard prenatal supplements often contain minimal or no choline. During gestation, choline is transported across the placenta to support fetal membrane synthesis, lipid metabolism, brain development, and epigenetic regulation through its role in one-carbon metabolism. Postnatally, maternal demands surge as large quantities of choline must be mobilised from maternal stores in the liver and secreted into breastmilk to sustain rapid postnatal growth. 
This high demand can lead to maternal choline depletion and influence metabolic health of the mother and her offspring. 

We hypothesise that disruption of maternal one-carbon metabolism alters choline availability during the perinatal period, changing nutritional and epigenetic signals that are received by the offspring and thereby influencing lifelong metabolic health.

The project will integrate two complementary mouse models: a maternal dietary choline restriction model and a genetic mouse line (Mtrrgt) with impaired one-carbon metabolism. The main aims of this project are:

1. To uncover how choline is allocated across the perinatal period and governed by maternal liver metabolism. The student will define how maternal liver metabolism shifts from supporting placental choline transport during gestation to driving mammary gland choline secretion during lactation. By quantifying choline metabolite profiles in maternal blood, the placenta, and milk alongside assessing the expression of tissue-specific choline transporters, we will uncover the mechanisms governing maternal choline partitioning before and after birth.

2. To identify potential epigenetic mechanisms that link pre- and postnatal choline exposure to long-term metabolic programming in offspring. The student will investigate how temporal changes in maternal dietary choline availability (i.e., during pregnancy, during lactation, and during pregnancy + lactation) influence epigenetic regulation of gene expression in metabolic tissues. 

3. To determine the degree to which changes in milk choline composition influences offspring growth and development. The student will utilise genetic and cross-fostering techniques to distinguish between prenatal from postnatal influences of choline on development and epigenetic regulation.

Overall, this PhD project will establish a systems-level approach to better understand the multi-organ network that governs the flow of essential nutrients, such as choline, from the maternal liver to the placenta and mammary gland to continuously support and program offspring metabolic health during the perinatal period.

Candidate background

While all training required for this project will be provided, experience in mouse handling and/or wet-lab experience would be advantageous.

References

  1. Padmanabhan, N., et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155(1):81-93. (2013)
  2. Sowton, A. P. et al. Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice. Mol. Genet. Metab. Rep. 23, 100580 (2020).
  3. Obeid, R. et al. A Narrative Review on Maternal Choline Intake and Liver Function of the Fetus and the Infant; Implications for Research, Policy, and Practice. Nutrients 2024, Vol. 16, Page 260 16, 260 (2024).
  4. AlSulaiti B, Ferguson-Smith AC, Hanin G. From mammary glands to nutrients: genetic insights into milk composition. Biol Reprod. (2026). doi: 10.1093/biolre/ioaf237. PMID: 41128813.
  5. Hanin G, Costello KR, Tavares H, AlSulaiti B, Patel S, Edwards CA, Ferguson-Smith AC (2025).  Dynamic allelic expression in mouse mammary gland across the adult developmental cycle. Nucleic Acids Research 
    DOI: 10.1093/nar/gkaf804