Cellular and molecular insights into Hox protein action

Abstract

Hox genes encode homeodomain transcription factors that control morphogenesis and have established functions in development and evolution. Hox proteins have remained enigmatic with regard to the molecular mechanisms that endow them with specific and diverse functions, and to the cellular functions that they control. Here, we review recent examples of Hox-controlled cellular functions that highlight their versatile and highly context-dependent activity. This provides the setting to discuss how Hox proteins control morphogenesis and organogenesis. We then summarise the molecular modalities underlying Hox protein function, in particular in light of current models of transcription factor function. Finally, we discuss how functional divergence between Hox proteins might be achieved to give rise to the many facets of their action.

The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

“…Moreover, a ranked list of genes that are ordered based on the BET binding score within the promoter region of all annotated genes shows that an unusually large number of the highestranking promoters are derived from HOX genes [26]. Thirty-nine HOX genes that are arranged in four clusters on the mammalian genome encode transcription factors that determine cell and tissue identities in the embryo during development and in the adult [56][57][58]. Because the Drosophila FSH, a counterpart of mammalian BET proteins, has been reported as crucial for the activation of the Ultrabithorax HOX gene [46,59], the regulatory mechanism of HOX expression by BET proteins might be conserved across species.…”

KPC2 relocalizes HOXA2 to the cytoplasm and decreases its transcriptional activity

“…As transcription factors, their transcriptional activity should be finely tuned to properly control the vast range of processes under their control. In fact, Hox proteins have been shown to display versatile activities according to the multiple cellular contexts they are involved in [4] and subtle deregulation of Hox expression can alter development processes or cell fates and lead to malformations or pathologies [44]. At a protein level, intra-cellular localization or stabilization versus degradation are ways to control transcription factor activities which have barely been addressed for Hox proteins.…”

“…For example, knockout mice for Hoxa2 display cranial transformations caused by the replacement of second branchial arch derivatives by skeletal elements typical of the first branchial arch in a mirror image configuration [2,3]. In addition to their function as homeotic genes in patterning embryonic territories, Hox genes have also been reported to control multiple events in later organogenesis and differentiation sequences up to adulthood (reviewed in [4]). …”

Chromosome folding and its regulation in health and disease

“…The mechanisms controlling cell health often involve transcription factors such as those encoded by the HOX genes, which function during development and in adult tissues. The HOX protein family controls morphogenesis during development by providing information necessary to define and establish territories along body axes [1]. In adults, the HOX transcription factors are important to maintain and regulate the stem cell pool of tissues, where they drive differentiation along defined lineages required for tissue repair and regeneration [2].…”