A TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm

Luca Mariani,Xiaogang Guo,Selgin Deniz Çakal,Elisabetta Ferretti,Niels Alvaro Menezes,Qinhu Wang,Anna Maria Drozd

doi:10.1038/s41467-021-25370-4

Abstract

One fundamental yet unresolved question in biology remains how cells interpret the same signalling cues in a context-dependent manner resulting in lineage specification. A key step for decoding signalling cues is the establishment of a permissive chromatin environment at lineage-specific genes triggering transcriptional responses to inductive signals. For instance, bipotent neuromesodermal progenitors (NMPs) are equipped with a WNT-decoding module, which relies on TCFs/LEF activity to sustain both NMP expansion and paraxial mesoderm differentiation. However, how WNT signalling activates lineage specific genes in a temporal manner remains unclear. Here, we demonstrate that paraxial mesoderm induction relies on the TALE/HOX combinatorial activity that simultaneously represses NMP genes and activates the differentiation program. We identify the BRACHYURY-TALE/HOX code that destabilizes the nucleosomes at WNT-responsive regions and establishes the permissive chromatin landscape for de novo recruitment of the WNT-effector LEF1, unlocking the WNT-mediated transcriptional program that drives NMPs towards the paraxial mesodermal fate.

Highlights

One fundamental yet unresolved question in biology remains how cells interpret the same signalling cues in a context-dependent manner resulting in lineage specification
Focussing on neuromesodermal progenitors (NMPs), mesodermal progenitor cells (MPCs) and pre-somitic mesoderm (PSM) cell populations revealed that the Pbx2−/− double-knockout (Pbx-DKO) and Pbx2+/− compound mutant (Pbx-com) NMPs and MPCs/pPSM clusters included cells that exhibited a mixed NMP/MPC profile, expressing high levels of T-Bra, Sox[2], Wnt3a, Tbx[6] and 5′ Hox genes (Fig. 1g and Supplementary Fig. 1f–h)
We established that TALE/HOX and WNT signalling work through a common genetic code that simultaneously represses NMP genes and activates the PSM differentiation programme

Summary

Introduction

One fundamental yet unresolved question in biology remains how cells interpret the same signalling cues in a context-dependent manner resulting in lineage specification. We identify the BRACHYURY-TALE/HOX code that destabilizes the nucleosomes at WNT-responsive regions and establishes the permissive chromatin landscape for de novo recruitment of the WNT-effector LEF1, unlocking the WNTmediated transcriptional program that drives NMPs towards the paraxial mesodermal fate. Compound deletion of PBX1 and PBX2 (hereafter PBX) uncovers a crucial role for these factors in axial/appendicular patterning[24,25], a surprisingly late phenotype as they are widely expressed at earlier embryonic stages[26] Their role in mesodermal lineage specification remains elusive. Using single-cell sequencing, chromatin accessibility analyses and iterative rounds of DNA:protein interaction assays, we demonstrate that TALE/HOX proteins generate the DNA-binding context for the recruitment of the WNTeffector LEF1, and promote the expression of PSM genes, including the master regulator Mesogenin[1] (Msgn1)[10,15]. TALE/HOX act as a molecular switch that triggers alternative WNT signalling cellular responses, unlocking PSM genes and promoting somite formation

Methods

Results

Conclusion