HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours
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Cellular and Molecular Life Sciences
REVIEW
HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours Céline S. Gonçalves1,2 · Elisa Le Boiteux3 · Philippe Arnaud3 · Bruno M. Costa1,2 Received: 25 October 2019 / Revised: 10 March 2020 / Accepted: 17 March 2020 © Springer Nature Switzerland AG 2020
Abstract HOX genes encode a family of evolutionarily conserved homeodomain transcription factors that are crucial both during development and adult life. In humans, 39 HOX genes are arranged in four clusters (HOXA, B, C, and D) in chromosomes 7, 17, 12, and 2, respectively. During embryonic development, particular epigenetic states accompany their expression along the anterior–posterior body axis. This tightly regulated temporal–spatial expression pattern reflects their relative chromosomal localization, and is critical for normal embryonic brain development when HOX genes are mainly expressed in the hindbrain and mostly absent in the forebrain region. Epigenetic marks, mostly polycomb-associated, are dynamically regulated at HOX loci and regulatory regions to ensure the finely tuned HOX activation and repression, highlighting a crucial epigenetic plasticity necessary for homeostatic development. HOX genes are essentially absent in healthy adult brain, whereas they are detected in malignant brain tumours, namely gliomas, where HOX genes display critical roles by regulating several hallmarks of cancer. Here, we review the major mechanisms involved in HOX genes (de)regulation in the brain, from embryonic to adult stages, in physiological and oncologic conditions. We focus particularly on the emerging causes of HOX gene deregulation in glioma, as well as on their functional and clinical implications. Keywords Glioma · Epigenetics · Transcriptional regulation · Neurodevelopment · Homeobox Abbreviations 3C Chromosome conformation capture 3D Three-dimensional 4C-seq Circularized chromosome conformation capture with deep sequencing 5C Chromosome conformation capture carbon copy AQB AC1Q3QWB drug CAM Chicken chorioallantoic membrane Céline S. Gonçalves and Elisa Le Boiteux have equally contributed to this work. Philippe Arnaud and Bruno M. Costa are co-senior authors. * Bruno M. Costa [email protected] 1
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710‑057 Braga, Portugal
2
ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
3
Université Clermont Auvergne, CNRS, INSERM-iGReD, Clermont‑Ferrand, France
CGGA Chinese Glioma Genome Atlas ChIP Chromatin immunoprecipitation CHROMO Chromatin organization modifier CNS Central nervous system CNV Copy-number variations COMPASS Complex proteins associated with Set1 DNA Deoxyribonucleic acid ESCs Embryonic stem cells GBM Glioblastoma G-CIMP Glioma CpG island methylator phenotype GSCs GBM stem cells H2AK119ub Ubiquitination of H2AK119 residues H3K27ac Histone H3 lysine 27 acetylation H3K27me3 Histone H3 lysine 27 trimethyla
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