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HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

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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.

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Fig. 1

(data adapted from Philippidou, Dasen [89])

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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

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 trimethylation

H3K4me3:

Histone H3 lysine 4 trimethylation

Hi-C:

Chromosome capture followed by high-throughput sequencing

HOX:

Homeobox

HUVEC:

Human umbilical vein endothelial cells

lncRNA:

Long non-coding RNA

miRNAs:

Micro-RNA

mRNA:

Messenger RNA

OS:

Overall survival

PARs:

Promoter-associated RNAs

PcG:

Polycomb group

PCR:

Polymerase chain reaction

PDX:

Patient-derived xenograft

PRE:

Polycomb-responsive element

RA:

Retinoic acid

RNA:

Ribonucleic acid

SINE:

Short interspersed nuclear elements

TAD:

Topological associating domain

TCGA:

The Cancer Genome Atlas

TMZ:

Temozolomide

TrxG:

Trithorax-group proteins

TSS:

Transcription start sites

WHO:

World Health Organization

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Author notes

  1. Céline S. Gonçalves and Elisa Le Boiteux have equally contributed to this work.

  2. Philippe Arnaud and Bruno M. Costa are co-senior authors.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal

    Céline S. Gonçalves & Bruno M. Costa

  2. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Céline S. Gonçalves & Bruno M. Costa

  3. Université Clermont Auvergne, CNRS, INSERM-iGReD, Clermont-Ferrand, France

    Elisa Le Boiteux & Philippe Arnaud

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  1. Céline S. Gonçalves
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  2. Elisa Le Boiteux
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  4. Bruno M. Costa
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Gonçalves, C.S., Le Boiteux, E., Arnaud, P. et al. HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours. Cell. Mol. Life Sci. 77, 3797–3821 (2020). https://doi.org/10.1007/s00018-020-03508-9

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