Boundaries mediate long-distance interactions between enhancers and promoters in the Drosophila Bithorax complex.

Nikolay Postika,Paul Schedl,Martin Müller,Pavel Georgiev,Mario Metzler,Markus Affolter,Olga Kyrchanova,Maria Cristina Gambetta

doi:10.1371/journal.pgen.1007702

Nikolay Postika, Paul Schedl + Show 6 more

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https://doi.org/10.1371/journal.pgen.1007702

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Abstract

Drosophila bithorax complex (BX-C) is one of the best model systems for studying the role of boundaries (insulators) in gene regulation. Expression of three homeotic genes, Ubx, abd-A, and Abd-B, is orchestrated by nine parasegment-specific regulatory domains. These domains are flanked by boundary elements, which function to block crosstalk between adjacent domains, ensuring that they can act autonomously. Paradoxically, seven of the BX-C regulatory domains are separated from their gene target by at least one boundary, and must “jump over” the intervening boundaries. To understand the jumping mechanism, the Mcp boundary was replaced with Fab-7 and Fab-8. Mcp is located between the iab-4 and iab-5 domains, and defines the border between the set of regulatory domains controlling abd-A and Abd-B. When Mcp is replaced by Fab-7 or Fab-8, they direct the iab-4 domain (which regulates abd-A) to inappropriately activate Abd-B in abdominal segment A4. For the Fab-8 replacement, ectopic induction was only observed when it was inserted in the same orientation as the endogenous Fab-8 boundary. A similar orientation dependence for bypass activity was observed when Fab-7 was replaced by Fab-8. Thus, boundaries perform two opposite functions in the context of BX-C–they block crosstalk between neighboring regulatory domains, but at the same time actively facilitate long distance communication between the regulatory domains and their respective target genes.

Highlights

The three homeotic (HOX) genes in the Drosophila Bithorax complex (BX-C), Ultrabithorax (Ubx), abdominal-A and Abdominal-B (Abd-B), are responsible for specifying cell identity in parasegments (PS) 5–14, which form the posterior half of the thorax and all of the abdominal segments of the adult fly [1,2,3]
Drosophila bithorax complex (BX-C) is one of a few examples demonstrating in vivo role of boundary/insulator elements in organization of independent chromatin domains
BXC contains three HOX genes, whose parasegment-specific pattern is controlled by cis-regulatory domains flanked by boundary/insulator elements

Summary

Introduction

The three homeotic (HOX) genes in the Drosophila Bithorax complex (BX-C), Ultrabithorax (Ubx), abdominal-A (abd-A) and Abdominal-B (Abd-B), are responsible for specifying cell identity in parasegments (PS) 5–14, which form the posterior half of the thorax and all of the abdominal segments of the adult fly [1,2,3]. Abd-B is regulated by four domains, iab-5, iab-6, iab-7 and iab, which control expression in PS10, PS11, PS12 and PS13 respectively [6,11,12]. A combination of gap and pair-rule proteins interact with initiation elements in each regulatory domain, setting the domain in the on or off state. In PS10, for example, the iab-5 domain, which regulates Abd-B, is activated by its initiator element, while the more distal Abd-B domains, iab-6 to iab-8 are set in the off state (Fig 1B). Once the gap and pair-rule gene proteins disappear during gastrulation, the on and off states of the regulatory domains are maintained by Trithorax (Trx) and Polycomb (PcG) group proteins, respectively [16,17]

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