7/8 To gain further mechanistic insight, we designed mutagenesis and domain swap experiments in stem cells and animal models. This showed that recruitment of the chromatin remodelling complex NuRD is essential for SALL4 function in vivo.

6/8 Combining acute degradation with multi-omics and explainable machine learning, we uncovered a crucial role for dispersed SALL4 binding over gene bodies. SALL4 influences chromatin structure at both transcriptionally “active” and “silent” regions, indicating a primary action on the epigenome.

4/8 Additionally, we modelled patient variants in SALL4 and SALL1 using cellular and animal models, demonstrating that multimerisation is involved in the pathogenesis of both Okihiro (OS) and Townes-Brocks (TBS) syndromes.

3/8 We mapped an evolutionarily conserved Q-rich Interaction Domain (QID) responsible for the formation of tetrameric SALL complexes. Strikingly, mutation of this domain within SALL4 (forcing the protein to become monomeric) abolishes chromatin binding and mimics a complete knockout!

2/5 Our main finding is that TET proteins control the balance of differentiation between somatic and germline lineages. We found out that TET-deficient embryonic stem cells differentiate very efficiently into germ cells (PGCLCs) in vitro, at the expense of endoderm/mesoderm/ectoderm pathways.