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Queirós do Patrocínio Patraquim, Pedro Miguel.pdf (33.68 MB)

Molecular and developmental impact of RNA processing on mammalian Hox genes

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posted on 2023-06-09, 01:40 authored by Pedro Miguel Queirós do Patrocínio Patraquim
The Hox genes encode a family of evolutionarily conserved transcription factors whose differential expression along head-to-tail triggers distinct programs of cell differentiation along the body axis. Mutations affecting the expression of Hox genes disrupt normal development in animals as diverse as insects and mammals. Although the developmental, evolutionary and biomedical relevance of this gene family is indisputable, the understanding of the molecular mechanisms controlling Hox gene expression is still incomplete. In particular little is known about the ways Hox gene expression is controlled within developmental units such as the insect segments or the rhombomeres in the developing mammalian brain. Previous work in Drosophila showed that different RNA processing events including alternative transcription, alternative splicing and alternative polyadenylation can affect Hox gene expression during the development of complex tissues such as the nervous system showing that differential RNA processing contributes to the generation of elaborate Hox expression patterns in the fruitfly embryo. Here we explore the impact of RNA processing on the molecular functions and developmental expression of Hox genes in mammals. For this we apply a combination of bioinformatic and computational methods complemented by a series of experiments in mammalian cell culture. Our work shows, first, that RNA processing has a pervasive impact on the expression of murine and human Hox genes and that specific Hox RNA processing reactions are coupled to one another and have evolved in coordination with gene-duplication events. Second, we find that RNA processing affecting several independent Hox genes can lead to the generation of Hox protein isoforms that lack a DNA-binding unit (the Homeodomain) suggesting that protein isoforms that are able and unable to bind DNA might be produced during development; furthermore, experiments in cell culture suggest that shorter homeodomain-less isoforms can be generated from longer homeodomain-containing templates suggesting a novel mechanism of RNA processing predicted to substantially impact the biochemical functions of Hox proteins. Third, we find that Hox alternative polyadenylation leading to the production of different 3’ untranslated regions (3’ UTRs) in Hox mRNAs can explain the generation of complex spatial patterns of Hox expression in the mouse developing limbs and brain. Altogether, our work adds to the current understanding of the molecular control of Hox expression during mammalian development, showing that RNA processing can significantly impact the biochemical properties and expression of Hox proteins.


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