Regeneration, repair and remembering identity: the three Rs of Hox gene expression

Hox genes encode transcription factors that specify embryonic positional identity in cells and guide tissue differentiation. Recent advances have greatly increased our understanding of the epigenetic mechanisms that ensure the faithful expression of Hox genes in adult cells and which involve the interplay of histone methylation, demethylation and intergenic transcription of long non-coding RNAs. The transcriptional memory of Hox genes poses both an opportunity and a challenge for regenerative medicine. Matching the positional identity of transplanted stem cells with that of the host environment, as reflected by their respective Hox profiles, is likely to be required to achieve regenerative healing. Strategies to manipulate the plasticity of Hox gene expression will probably become a major focus in regenerative medicine.

Introduction

The discovery of genes that control embryonic body segment identity is one of the great triumphs of developmental biology. Recent studies have led to the realization that some of these same genes have ongoing and prominent functions in adult cells. The Hox genes in particular, which code for a large family of transcription factors, have key roles in embryonic segmental identity (Box 1, Figure 1; see http://www.youtube.com/watch?v=9k_oKK4Teco for a recent animated tribute), and their expression in adult cells constitutes a form of positional memory – an internal representation by a cell of where it is located within a multicellular organism.

The confluence of two areas of investigation has brought the transcriptional memory of Hox genes into focus. On the one hand, substantial progress has recently been made in unraveling mechanisms of epigenetic regulation of Hox genes. The fidelity of expression pattern of Hox genes is necessary for the normal homeostasis of adult tissues and organs, and mis-expression of Hox genes can readily lead to diseases such as cancer 1, 2. On the other hand, the positional memory of cells has important implications for the burgeoning field of regenerative medicine. A proper pattern of Hox genes could be programmed to make the desired tissues; conversely, the inability to erase or transcend a fixed pattern of Hox genes might be a key factor limiting regeneration in mammals. We describe here newly recognized epigenetic mechanisms that make the transcriptional memory of Hox particularly robust, and the implications of the cellular memory of Hox expression for tissue homeostasis and developmental plasticity that could prove to be necessary for tissue regeneration.