Conserved boundary elements from the Hox complex of mosquito, Anopheles gambiae

Abstract

The conservation of hox genes as well as their genomic organization across the phyla suggests that this system of anterior–posterior axis formation arose early during evolution and has come under strong selection pressure. Studies in the split Hox cluster of Drosophila have shown that proper expression of hox genes is dependent on chromatin domain boundaries that prevent inappropriate interactions among different types of cis-regulatory elements. To investigate whether boundary function and their role in regulation of hox genes is conserved in insects with intact Hox clusters, we used an algorithm to locate potential boundary elements in the Hox complex of mosquito, Anopheles gambiae. Several potential boundary elements were identified that could be tested for their functional conservation. Comparative analysis revealed that like Drosophila, the bithorax region in A. gambiae contains an extensive array of boundaries and enhancers organized into domains. We analysed a subset of candidate boundary elements and show that they function as enhancer blockers in Drosophila. The functional conservation of boundary elements from mosquito in fly suggests that regulation of hox genes involving chromatin domain boundaries is an evolutionary conserved mechanism and points to an important role of such elements in key developmentally regulated loci.

The regulatory genome of the malaria vectorAnopheles gambiae: integrating chromatin accessibility and gene expression

“…To map active regulatory sites, we used An. gambiae enhancers predicted computationally by others from Drosophila enhancers (N=1,628), or from Drosophila enhancer motifs (N=51) (37,38), as well a few Anopheles enhancers identified previously by STARR-seq (N=6) (44) (see Supplementary Methods). Next, to generate a set of novel candidates, we downloaded D. melanogaster collections of enhancers (27), including some activity-based enhancer-target gene assignments (26).…”

“…Using our ATAC-seq data, we map in vivo 42% (708) of those 1,685 An. gambiae enhancers predicted bioinformatically (37,38,44). In addition, we found 1,122 potentially novel An.…”

“…Of the 1,685 An. gambiae enhancers suggested from previous studies (37,38,44), mostly based on computational predictions, 42% (708) were identified as THSs ( Supplementary Table S11), and therefore may correspond to active enhancers in the tissues assayed here. Furthermore, using a homology approach and D. melanogaster enhancer maps such as the EnhancerAtlas (27) (see Methods and Supplementary Info), we predicted 1,122 novel enhancer-like regions.…”

Functional sub-division of the Drosophila genome via chromatin looping

“…Chromatin insulators were first discovered in Drosophila melanogaster and subsequently in a variety of organisms including yeast, mosquito, Xenopus, chicken, mice and humans suggesting their widespread importance in genome organization. [5][6][7][8][9][10][11] These elements exert their effects by preventing inappropriate crosstalk between genomic regions such as enhancers and promoters and active and silent states of the chromatin (Fig. 1).…”

The function of homeobox genes and lncRNAs in cancer

“…These genes most importantly function as transcriptional regulators during normal morphogenesis in the process of cell-to-cell communication, the modification of which may contribute to the development of cancer (40,41). The HOX gene homology domain is able to bind to specific DNA sequences and regulate gene transcription (42).…”