Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm

Hiroko Nomaru,Dario Righelli,Bernice E Morrow,Anelisa G Dantas,Andrea Cirino,Hansoo Song,Deyou Zheng,Claudia Angelini,Chen-Leng Cai,Robert G Kelly,Wei Wang,Christopher De Bono,Silvia E Racedo,Lu Zhang,Yang Liu,Antonio Baldini,Lionel Christiaen

doi:10.1038/s41467-021-26966-6

Abstract

The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus. They are disrupted in patients with 22q11.2 deletion syndrome, due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we now identify a multilineage primed population within the cardiopharyngeal mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells. The multilineage primed cells are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of cardiopharyngeal mesoderm progenitors. Tbx1 regulates the maturation of multilineage primed progenitor cells to cardiopharyngeal mesoderm derivatives while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance of gene expression by direct and indirect regulation of enriched genes in multilineage primed progenitors and downstream pathways, partly through altering chromatin accessibility, the perturbation of which can lead to congenital defects in individuals with 22q11.2 deletion syndrome.

Highlights

The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus
We suggest that C15 as a multilineage primed progenitor (MLP) population within the cardiopharyngeal mesoderm (CPM)
We discovered that MLPs are localized bilaterally within the posterior nascent mesoderm of the pharyngeal apparatus

Summary

Introduction

The poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus. They are disrupted in patients with 22q11.2 deletion syndrome, due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Using single cell RNA-sequencing, we identify a multilineage primed population within the cardiopharyngeal mesoderm, marked by Tbx[1], which has bipotent properties to form cardiac and branchiomeric muscle cells. The Tbx[1] gene, encoding a T-box transcription factor, and gene haploinsufficient in 22q11.2 deletion syndrome (22q11.2DS), is expressed in the CPM and is required for cardiac outflow tract and BrM development[2], implicating its essential roles in the CPM. We do not yet understand the functions of Tbx[1] on a single-cell level, which is needed to elucidate the true molecular pathogenesis of

Methods

Results

Conclusion