Project Reference: TRG27-GRD-MR1

Project title: Dissecting MLL3/4-mediated enhancer regulation during early human development

Project outline

During early human development, the pluripotent epiblast gives rise to all embryonic lineages through tightly regulated changes in gene expression. The establishment of these developmental programmes largely relies on epigenetic regulation at gene regulatory elements called enhancers, yet the underlying molecular mechanisms are poorly understood.

During development, enhancers transition between repressed, primed, and active states. The histone methyltransferases MLL3 and MLL4 bind active and primed enhancers and deposit the histone H3 lysine 4 monomethylation (H3K4me1) mark. Moreover, accumulating evidence suggests that MLL3/4 have functions beyond histone modification. However, the functional importance of H3K4me1 and the non-catalytic roles of MLL3/4 remain unresolved.

This PhD project will define the role of MLL3/4 during human development. Human pluripotent stem cells will be used to model the earliest cell fate decisions of the human embryo. MLL3/4 function will be perturbed using genetic knockouts, inducible degrons and catalytic mutants. Inducible degrons will define when MLL3/4 are required during development. Catalytic mutants will reveal how they regulate enhancer function by separating the roles of H3K4me1 from the non-catalytic activities of MLL3/4.

The consequences of MLL3/4 perturbations will be investigated at both the cellular and molecular levels. Functional differentiation assays will determine how the loss of MLL3/4 activities affects developmental potential, while genome-wide profiling of epigenetic changes and gene expression programmes will uncover the molecular mechanisms underlying these phenotypes.

This project will uncover how MLL3/4 regulate human cell fate decisions, providing fundamental insights into the epigenetic mechanisms that control early human development. This experience will train the student in both stem cell biology and computational genomics, launching their research career in a supportive environment.

Principal Supervisor

Dr Maria Rostovskaya

Email address: mr631@cam.ac.uk

Department / Partner Institute: Gurdon Institute

Website: https://www.gurdon.cam.ac.uk/people/maria-rostovskaya/

BBSRC strategic theme

Understanding the rules of life