Chromatin boundary elements organize genomic architecture and developmental gene regulation in Drosophila Hox clusters

Abstract

The three-dimensional (3D) organization of the eukaryotic genome is critical for its proper function. Evidence suggests that extensive chromatin loops form the building blocks of the genomic architecture, separating genes and gene clusters into distinct functional domains. These loops are anchored in part by a special type of DNA elements called chromatin boundary elements (CBEs). CBEs were originally found to insulate neighboring genes by blocking influences of transcriptional enhancers or the spread of silent chromatin. However, recent results show that chromatin loops can also play a positive role in gene regulation by looping out intervening DNA and “delivering” remote enhancers to gene promoters. In addition, studies from human and model organisms indicate that the configuration of chromatin loops, many of which are tethered by CBEs, is dynamically regulated during cell differentiation. In particular, a recent work by Li et al has shown that the SF1 boundary, located in the Drosophila Hox cluster, regulates local genes by tethering different subsets of chromatin loops: One subset enclose a neighboring gene ftz, limiting its access by the surrounding Scr enhancers and restrict the spread of repressive histones during early embryogenesis; and the other loops subdivide the Scr regulatory region into independent domains of enhancer accessibility. The enhancer-blocking activity of these CBE elements varies greatly in strength and tissue distribution. Further, tandem pairing of SF1 and SF2 facilitate the bypass of distal enhancers in transgenic flies, providing a mechanism for endogenous enhancers to circumvent genomic interruptions resulting from chromosomal rearrangement. This study demonstrates how a network of chromatin boundaries, centrally organized by SF1, can remodel the 3D genome to facilitate gene regulation during development.

Keywords: Chromatin boundary element, Insulator, CTCF, Chromatin loop domains, Drosophila, Hox genes

Core tip: Genomic organization in higher eukaryotes needs to fulfill at least three distinct functions: Gene compaction, gene insulation and gene regulation. Chromatin loops appear to be a common structural unit that serves all these functions. A recent study has characterized a series of chromatin boundary elements (CBEs) in the Drosophila Hox cluster. Selective and dynamic interactions between these CBEs tether chromatin loops that not only insulate neighboring genes, but also organize enhancer traffic to regulate gene expression during development.