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Comparative Transcriptomics Analyses across Species, Organs, and Developmental Stages Reveal Functionally Constrained lncRNAs

Fabrice Daniel Darbellay, Anamaria Necsulea

The functionality of long noncoding RNAs (lncRNAs) is disputed. In general, lncRNAs are under weak selective pressures, suggesting that the majority of lncRNAs may be nonfunctional. However, although some surveys showed negligible phenotypic effects upon lncRNA perturbation, key biological roles were demonstrated for individual lncRNAs. Most lncRNAs with proven functions were implicated in gene expression regulation, in pathways related to cellular pluripotency, differentiation, and organ morphogenesis, suggesting that functional lncRNAs may be more abundant in embryonic development, rather than in adult organs. To test this hypothesis, we perform a multidimensional comparative transcriptomics analysis, across five developmental time points (two embryonic stages, newborn, adult, and aged individuals), four organs (brain, kidney, liver, and testes), and three species (mouse, rat, and chicken). We find that, overwhelmingly, lncRNAs are preferentially expressed in adult and aged testes, consistent with the presence of permissive transcription during spermatogenesis. LncRNAs are often differentially expressed among developmental stages and are less abundant in embryos and newborns compared with adult individuals, in agreement with a requirement for tighter expression control and less tolerance for noisy transcription early in development. For differentially expressed lncRNAs, we find that the patterns of expression variation among developmental stages are generally conserved between mouse and rat. Moreover, lncRNAs expressed above noise levels in somatic organs and during development show higher evolutionary conservation, in particular, at their promoter regions. Thus, we show that functionally constrained lncRNA loci are enriched in developing organs, and we suggest that many of these loci may function in an RNA-independent manner.

OXFORD UNIV PRESS2020

Control of growth and gut maturation by &ITHoxD&IT genes and the associated lncRNA &ITHaglr&IT

Fabrice Daniel Darbellay, Denis Duboule, Anamaria Necsulea, Jozsef Zakany

During embryonic development, Hox genes participate in the building of a functional digestive system in metazoans, and genetic conditions involving these genes lead to important, sometimes lethal,growth retardation. Recently, this phenotype was obtained after deletion of Haglr, the Hoxd antisense growth-associated long non-coding RNA (IncRNA) located between Hoxd1 and Hoxd3. In this study, we have analyzed the function of Hoxd genes in delayed growth trajectories by looking at several nested targeted deficiencies of the mouse HoxD cluster. Mutant pups were severely stunted during the suckling period, but many recovered after weaning. After comparing seven distinct HoxD alleles, including CRISPR/Cas9 deletions involving Haglr, we identified Hoxd3 as the critical component for the gut to maintain milk-digestive competence. This essential function could be abrogated by the dominant-negative effect of HOXD10 as shown by a genetic rescue approach, thus further illustrating the importance of posterior prevalence in Hox gene function. A role for the IncRNA Haglr in the control of post-natal growth could not be corroborated.

Proceedings of the National Academy of Sciences2017

A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus

Leonardo Beccari, Denis Duboule, Nicolas Lonfat, Anamaria Necsulea, Edgardo Rodriguez Carballo, Nayuta Yakushiji

During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.

Cold Spring Harbor Laboratory2016

Comparative Transcriptomics Analyses across Species, Organs, and Developmental Stages Reveal Functionally Constrained lncRNAs

Fabrice Daniel Darbellay, Anamaria Necsulea

OXFORD UNIV PRESS2020