Krezel, W. | Search bioRxiv

bioRxiv2023

Torsion of the heart tube by shortage of progenitor cells : identification of Greb1l as a genetic determinant of criss-cross heart in mice

Despite their burden and impact, most congenital defects remain poorly understood by lack of knowledge of the embryological mechanisms. Here, we identify Greb1l mutants as the first mouse model of criss-cross heart. Based on 3D quantifications of shape changes, we demonstrate that torsion of the atrioventricular canal occurs together with supero-inferior ventricles at E10.5, after heart looping. Mutants phenocopy specific features of partial deficiency in retinoic acid signalling, suggesting that GREB1L is a novel modulator of this signalling. Spatio-temporal gene mapping and cross-correlated transcriptomic analyses further reveal the role of Greb1l in maintaining a pool of precursor cells during heart tube elongation, by controlling ribosome biogenesis and cell differentiation. Growth arrest and malposition of the outflow tract are predictive of abnormal tube remodelling in mutants. Our work on a rare cardiac malformation opens novel perspectives on the origin of a broader spectrum of congenital defects associated with GREB1L in humans. HighlightsO_LIGreb1l inactivation is the first model of criss-cross heart C_LIO_LIGrowth arrest of the outflow tract and reduced pole distance are predictive of the torsion of the atrioventricular canal, and also account for associated defects of supero-inferior ventricles and malposition of the great vessels C_LIO_LIVentricle position needs to be maintained after heart looping C_LIO_LIGREB1L, which is associated in humans with a spectrum of congenital defects, is required to maintain precursor cells, by promoting ribosome biogenesis and restricting cell differentiation. C_LIO_LIGREB1L is a novel factor involved in retinoic acid signalling. C_LI In BriefGREB1L is associated with a spectrum of congenital defects in humans. Bernheim et al now uncover its function in maintaining a reservoir of precursor cells. Inactivation of Greb1l in the mouse impairs the elongation of the heart tube leading to criss-cross heart with supero-inferior ventricles.

developmental biology↗

bioRxiv2021

Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation

A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.

genetics↗