Transcriptional Regulation and Implications for Controlling Hox Gene Expression

Abstract

Hox genes play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. Nested domains of Hox expression generate a combinatorial code that provides a molecular framework for specifying the properties of tissues along the A-P axis. Hence, it is important to understand the regulatory mechanisms that coordinately control the precise patterns of the transcription of clustered Hox genes required for their roles in development. New insights are emerging about the dynamics and molecular mechanisms governing transcriptional regulation, and there is interest in understanding how these may play a role in contributing to the regulation of the expression of the clustered Hox genes. In this review, we summarize some of the recent findings, ideas and emerging mechanisms underlying the regulation of transcription in general and consider how they may be relevant to understanding the transcriptional regulation of Hox genes.

Keywords: Hox genes; coordinate regulation; enhancers; gene regulation; nascent transcripts; transcription factors; transcriptional regulation.

Figure 1

The mammalian Hox gene clusters and the conserved signaling pathways that play a role in defining the Hox gene expression profiles. (A) In mammals, there are four clusters of Hox genes, each on different chromosomes. They exhibit spatial and temporal collinearity, such that 3′ Hox genes are expressed early in development as well as more anteriorly in an embryo generating nested domains of expression as depicted in the drawing of an E10 mouse embryo. (B) The restricted domains of Hox expression arise through an integration of signaling molecules such as RA, FGF and WNT, which are expressed in gradients along the embryonic axis. PSM, presomitic mesoderm.

Figure 2

Transcriptional complexity of the Hoxb gene cluster and binding of HOX Transcription factors to DNA (A) A drawing of the Hoxb gene cluster to illustrate that non-coding RNAs as well as enhancers that contain RAREs (Retinoic Acid Response Elements) are interspersed within the coding Hox genes. The enlargement of the Hoxb4-Hoxb5 region shows the complexity within the region that contains three RAREs, two present upstream of Hoxb4 and one present downstream of Hoxb4 and two non-coding RNAs, Hobbit and HoxBlinc. Brown boxes flank the cluster depict boundary elements, colored squares are different Hox genes, pink boxes are non-coding RNAs, and green lines represent RARE enhancers. (B) Depicts the consensus DNA binding sites for HOX proteins and their binding partners, the TALE proteins PBX and MEIS. HOX proteins can bind on Hox-Pbx bipartite sites, or they can bind on DNA in ternary complexes along with both PBX and MEIS. Blue ovals are HOX proteins, and grey ovals are TALE protein binding partners.

Figure 3

Schematic of how the chromatin may loop to activate genes within the transcriptionally complex Hoxb gene cluster (A) Different loop confirmations envisioned for activation of specific genes within the Hoxb cluster, which contains several enhancer elements (such as DE, B4U and ENE) as well as coding and non-coding genes. (B) Inference [41,44] for how nascent Hoxb transcripts may promote condensate formation to increase nascent transcription, and subsequently, how an increased number of nascent transcripts may inhibit transcription by promoting condensate dissolution. Brown boxes at cluster edges depict boundary elements, blue and pink colored ovals depict coding genes and non-coding RNAs, respectively, and green ovals are RARE enhancers.