Research description

Our scientific goal is to gain a deeper molecular understanding of how signalling cues and epigenetic changes during early mouse development are integrated to regulate transcription factor specificity. Transcription factor (TF) binding is sequence specific with each TF possessing its distinct DNA binding motif. However, variations in binding site occupancy and thus TF functions in different cell types imply additional regulatory mechanisms for TF binding specificity. One key example for variation in TF functions occurs during early embryonic development, when two of the most fundamental lineage decisions, segregation between inner cell mass (ICM) and trophectoderm (TE), and specification of the three germ layers neuroectoderm (NE), mesoderm and endoderm (ME), are made. These two lineage decisions are regulated by overlapping sets of transcription factors, including CDX and TBX factors. However, the underlying mechanisms that account for differences of TF functions between these two lineage choices and the integration of signalling cascades and epigenetic regulation are largely unexplored.

Key words

Epigenetic mechanisms, transcription factor specificity, early mouse development, lineage segregation, mouse embryonic stem cells

Signaling-mediated priming of enhancer landscapes guides cell lineage specification

Early embryonic mouse development is a process of successive lineage restrictions from a totipotent zygote to pluripotent epiblast and further differentiated cells. This lineage restriction is tightly regulated by epigenetic control mechanisms and signaling cascades in conjunction with transcription factors (TFs). Transcription factor binding is sequence specific with each transcription factor possessing its distinct DNA binding motif. However, variations in binding site occupancy in different cell types imply additional regulatory mechanisms for TF binding specificity. During gastrulation signaling cascades induce the expression of lineage specific TFs. Interestingly, two of the most fundamental lineage decisions of mammalian embryos, segregation between inner cell mass (ICM) and trophectoderm (TE), and specification of the three germ layers neuroectoderm (NE), mesoderm and endoderm (ME), are regulated by overlapping sets of transcription factors, including CDX and TBX factors. Of note, the underlying mechanisms that account for differences of transcription factor functions between these two lineage choices and the integration of signaling cascades and epigenetic regulation are largely unexplored.

10 selected publications

• Eomes restricts Brachyury function at the onset of mammalian gastrulation.Schüle KM*^,1, Weckerle J, Probst S, Wehmeyer AE, Zissel L, Schröder CM, Tekman M, Kim G-J. Schlägl I-M, Sagar, Arnold SJ¹ (2023) bioRxiv doi.org/10.1101/2023.01.27.525830, Developmental Cell: in revisions
• Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity. Wang S, Klein SO, Urban S, Staudt M, Barthes NPF, Willmann D, Bacher J, Sum M, Bauer H, Peng L, Rennar GA, Gratzke C, Schüle KM, Zhang L, Einsle O, Greschik H, MacLeod C, Thomson CG, Jung M, Eric Metzger E, Schüle R (2023) Nature Communications 15 (43), doi: 0.1038/s41467-023-44243-6
• Chimeric 3D gastruloids – a versatile tool for studies of mammalian peri-gastrulation development. Wehmeyer AE, Schüle KM, Conrad A, Schröder SM, Probst S, Arnold SJ (2022) Development 149, dev200812.
• GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells. Schüle KM*, Leichsenring M*, Andreani T, Vastolo V, Mallick M, Musheev MU, Karaulanov E, Niehrs C (2019) Genes and Development 33, 782-798
• NEIL1 and NEIL2 DNA glycosylases protect neural crest development against mitochondrial oxidative stress. Han D*, Schomacher L*, Schüle KM*, Mallick M, Musheev MU, Karaulanov E, Krebs L, von Seggern A, Niehrs C (2019) eLife 8, 49044
• Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Metzger E, Willmann D, McMillan J, Forne I, Metzger P, Gerhardt S, Petroll K, von Maessenhausen A, Urban S, Schott AK, Espejo A, Eberlin A, Wohlwend D, Schüle KM, Schleicher M, Perner S, Bedford MT, Jung M, Dengjel J, Flaig R, Imhof A, Einsle O, Schüle R (2016) Nature Structural & Molecular Biology 23, 132-139