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Trithorax group proteins: switching genes on and keeping them active

Nature Reviews Molecular Cell Biology volume 12, pages 799–814 (2011)Cite this article

Subjects

Key Points

  • Trithorax group (TrxG) proteins have been genetically defined as antagonistic regulators of Polycomb group (PcG) proteins, which maintain cellular memory. Now, we know that the TrxG proteins are a heterogeneous group that is additionally involved in tumorigenesis, cell cycle control, stem cell renewal, cell fate determination and differentiation.

  • TrxG proteins modify or remodel histones to activate genes and keep them active. They are recruited to their target genes by specific DNA sequences, pre-existing histone marks and non-coding RNAs.

  • TrxG complexes control the expression levels of major cell cycle regulators in a cell type-dependent manner. By targeting cyclin-dependent kinase inhibitors, TrxG proteins behave like essential integrators of cell cycle checkpoints.

  • TrxG activities are intimately connected with the main signalling pathways.

  • By regulating histone modification and nucleosome remodelling, TrxG proteins play an important part in the self-renewal and differentiation of embryonic stem cells, multiple types of adult stem cells and germ cells.

Abstract

Cellular memory is provided by two counteracting groups of chromatin proteins termed Trithorax group (TrxG) and Polycomb group (PcG) proteins. TrxG proteins activate transcription and are perhaps best known because of the involvement of the TrxG protein MLL in leukaemia. However, in terms of molecular analysis, they have lived in the shadow of their more famous counterparts, the PcG proteins. Recent advances have improved our understanding of TrxG protein function and demonstrated that the heterogeneous group of TrxG proteins is of critical importance in the epigenetic regulation of the cell cycle, senescence, DNA damage and stem cell biology.

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Figure 1: Classes of TrxG proteins and TrxG-containing complexes across species.
Figure 2: Multiple mechanisms recruit TrxG complexes to their target sites.
Figure 3: Histone crosstalk in TrxG-mediated gene activation.
Figure 4: Role of MLL proteins in cell cycle control.
Figure 5: Cell signalling and MLL.

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Acknowledgements

We apologize to those whose recent publications we were unable to cite owing to space limitations. N.I. was supported by a long-term European Molecular Biology Organization fellowship and by a fellowship from the Human Frontier Science Program Organization. The research of C.G. was supported by grants from the European Research Council (ERC-2008-AdG no. 232947), the Centre national de la recherche scientifique, the European Network of Excellence EpiGeneSys, the Agence Nationale de la Recherche and the Association pour la Recherche sur le Cancer.

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  1. Bernd Schuettengruber and Anne-Marie Martinez: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Génétique Humaine, CNRS, 141, Rue de la Cardonille, Montpellier Cedex 5, 34396, France

    Bernd Schuettengruber, Anne-Marie Martinez, Nicola Iovino & Giacomo Cavalli

  2. Université de Montpellier 2, Place Eugène Bataillon, Montpellier Cedex 5, 34095, France

    Anne-Marie Martinez

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Glossary

Epigenetic

A form of gene expression maintenance in which the heritable state of gene activity neither requires the continuous presence of the initiating signal nor involves changes in the DNA sequence.

Homeobox genes

(HOX genes). A family of genes that encode transcription factors which are essential for patterning along the anterior–posterior body axis.

Homeotic transformations

The consequences of mutations that lead to the transformation of the identity of one body segment into the identity of another.

SET domain

(Su(var)3-9, Enhancer of Zeste, Trithorax). A motif ∼130 amino acids in length that provides histone methyltransferase activity. It is found in many chromatin-associated proteins, including some Trithorax group and Polycomb group proteins.

MYST

A family of histone acetyltransferases that is defined by the founding members Moz, Ybf2 (Sas3), Sas2 and Tip60.

RAS signalling

An intracellular signal transduction pathway involving RAS. RAS activates many signalling cascades involved in multiple developmental events controlling cell proliferation, migration and survival.

SWI/SNF

(Switch/sucrose nonfermentable). A chromatin-remodelling complex family that was first identified genetically in yeast as a group of genes required for mating type switching and growth on alternative sugar sources to sucrose. This complex is required for the transcriptional activation of ∼7% of the genome.

Bromodomain

A conserved protein module, which was first identified in the Drosophila melanogaster protein Brahma and has subsequently been found in many chromatin-associated proteins. This domain can recognize acetyl-Lys motifs.

SANT domain

A conserved histone-binding domain that takes its name from the proteins in which it was initially identified: Swi3, ADA2, N-CoR and TFIIB.

Nucleosome-remodelling factor

(NURF). A chromatin-remodelling complex identified in Drosophila melanogaster and belonging to the imitation switch subfamily.

Chromodomain

A motif of ∼60 amino acids that is found in many chromatin-associated proteins and forms a binding pocket for methylated histone residues.

Bivalent chromatin domains

Domains that are characterized by the juxtaposition of active and inactive epigenetic histone marks.

Plant homeodomain finger

(PHD finger). A PHD-linked zinc-finger that chelates double zinc ions. This protein motif is found in many chromatin regulators and binds histones in a methylation-dependent or -independent manner.

Trans histone code

This term describes the fact that post-translational modifications on one histone tail can influence those on another, even when they are located on different histones, resulting in a specific gene expression output.

CDKI

(Cyclin-dependent kinase inhibitor). Members of the CIP and KIP family of CDKIs (p21, p27 and p57) inhibit CDK2- and CDK1-containing complexes, and members of the INK4 family (p15, p16, p18 and p19) inhibit cyclin D-containing complexes. Expression of CDKIs generally causes growth arrest and, when CDKIs are acting as tumour suppressors, may cause cell cycle arrest and apoptosis.

SCF and APC/C

(Skp–cullin–F box and anaphase-promoting complex (also known as the cyclosome)). Multiprotein E3 ubiquitin ligase complexes that are involved in the recognition and ubiquitylation of specific cell cycle target proteins for proteasomal degradation.

E3 ubiquitin ligases

Enzymes that target specific proteins for degradation by the proteasome by causing the attachment of ubiquitin to Lys residues on their substrates.

Cellular transformation

A change undergone by animal cells, caused by escape from control mechanisms (for example, upon infection by a cancer-causing virus). Transformed cells have increased growth potential, alterations in cell surface, karyotypic abnormalities and the ability to invade and metastasize.

ATR

(Ataxia-telangiectasia- and RAD3-related). A caffeine-sensitive, DNA-activated protein kinase that is involved in DNA damage checkpoints.

Radioresistant DNA synthesis

(RDS). When mutant cells fail to repress the firing of DNA replication origins in the presence of ionizing radiation-induced DNA damage.

Notch signalling

This pathway is a highly conserved intercellular signalling mechanism that is essential not only for cell proliferation but also for numerous cell fate-specification events.

Extracellular signal-regulated kinase

(ERK). A protein involved in a mitogen-activated protein kinase signal transduction pathway that functions in cellular proliferation, differentiation and survival. Its inappropriate activation is a common occurrence in the human cancers.

Nucleosomal response

The rapid phosphorylation of histone H3 that occurs concomitantly with the induction of immediate early genes, which is mediated through alternative mitogen-activated protein kinase cascades.

WNT–β-catenin pathway

A signalling pathway involving widely conserved secreted signalling molecules of the Wingless family, which regulate many processes during animal development.

JAK–STAT

(Janus kinase–signal transducer and activator of transcription). A rapid signal transduction pathway used by a range of cytokines and growth factors. Binding of a cytokine or growth factor to its receptor activates cytoplasmic JAK, which then phosphorylates STAT and triggers its translocation into the nucleus, where it induces the transcription of specific genes.

Neural progenitor cells

(NPCs). A stem cell type found in adult neural tissue that can give rise to neuron and supporting cells (glia). During development, NPCs produce the enormous diversity of neurons and glia in the developing central nervous system, and they have been also shown to engage in the replacement of dying neurons.

Long-term HSCs

(LT-HSCs). Haematopoietic stem cells that have long-term regeneration capacities and can restore the haematopoietic system of an irradiated mouse over months.

Short-term HSCs

(ST-HSCs). Haematopoietic stem cells that, under normal circumstances, cannot renew themselves over a long term. They are also referred to as progenitor or precursor cells, as they are relatively immature cells that are precursors to a fully differentiated cell of the same tissue type.

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Schuettengruber, B., Martinez, AM., Iovino, N. et al. Trithorax group proteins: switching genes on and keeping them active. Nat Rev Mol Cell Biol 12, 799–814 (2011). https://doi.org/10.1038/nrm3230

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