Genomic features of human limb specific enhancers

Abstract

To elucidate important cellular and molecular interactions that regulate patterning and skeletal development, vertebrate limbs served as a model organ. A growing body of evidence from detailed studies on a subset of limb regulators like the HOXD cluster or SHH, reveals the importance of enhancers in limb related developmental and disease processes. Exploiting the recent genome-wide availability of functionally confirmed enhancer dataset, this study establishes regulatory interactions for dozens of human limb developmental genes. From these data, it appears that the long-range regulatory interactions are fairly common during limb development. This observation highlights the significance of chromosomal breaks/translocations in human limb deformities. Transcriptional factor (TF) analysis predicts that the differentiation of early nascent limb-bud into future territories entail distinct TF interaction networks. Conclusively, an important motivation for annotating the human limb specific regulatory networks is to pave way for the systematic exploration of their role in disease and evolution.

Comparative genomic analysis of human GLI2 locus using slowly evolving fish revealed the ancestral gnathostome set of early developmental enhancers

“…For instance, enhancers have been reported to act at a distance of 2 Mb or more from target gene body. 35 , 36 Furthermore, expression of a typical animal gene is likely to be governed by multiple distinct enhancer elements and in some cases individual enhancers are known to regulate multiple genes. 35 , 37 Therefore, the association of functionally confirmed enhancers with their target genes have remained a challenging task.…”

“…Association of selected CNEs with their target gene is based on two filters such as comparative genomics and endogenous expression pattern analysis. 35 , 36 For this purpose human synteny map containing predicted CNEs loci was drafted using UCSC ( http://genome.ucsc.edu/ ) and Ensemble Genome Browser ( https://asia.ensembl.org ). These maps depict flanking genes located at a radius of 1 Mb.…”

“…It would be appropriate then to speculate that the target gene would also be the same between compared species. 35 , 36 Under these assumptions, a comparative picture of CNEs bearing human synteny map was comparatively analyzed in mice and spotted gar using multispecies view option in the Ensembl genome browser. Evolutionarily conserved physical linkage between CNE elements and one or more neighboring genes was taken as an evidence of functional association.…”

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

“…Over the last couple of decades, comparative genomic approaches have revealed numerous evolutionarily conserved cis ‐acting regulatory modules in vertebrates (CRMs) (Ali et al, 2016; Minhas et al, 2015; Paparidis et al, 2007). CNEs are enriched for CRMs with developmental enhancer activities (Boffelli et al, 2004; Pennacchio et al, 2006; Woolfe et al, 2005) and vertebrate genomes hold thousands of anciently conserved CNEs that frequently cluster near trans ‐developmental genes (Parveen et al, 2013; Woolfe et al, 2005).…”

Cis‐regulatory control of mammalian Trps1 gene expression

“…Predicted enhancers are frequently associated with a specific target gene body through a comparative syntenic investigation of the enhancer‐containing locus and an analysis of the endogenous expression patterns of neighboring genes (Ali et al, 2016; Parveen et al, 2013). In this study, the human locus (GRCh38: Chromosome 8: 115,408,496‐115,809,673) containing predicted TRSP1 CNE‐enhancers underwent syntenic comparison with other vertebrate species (Mouse and Zebrafish) using the region comparison option available at the Ensemble Genome Browser (https://asia.enemble.org) (Martin et al, 2022).…”