The transcription factor code: a beacon for histone methyltransferase docking

doi:10.1016/j.tcb.2021.04.001

Trends in Cell Biology

Volume 31, Issue 10, October 2021, Pages 792-800

https://doi.org/10.1016/j.tcb.2021.04.001 Get rights and content

Highlights

Lineage-instructive transcription factors (Lin-TFs) are able to drive cell fate changes by binding to sequence-specific motifs in gene regulatory elements (GREs).
Histone methyltransferases (HMTs) decorate histones at different GREs in different cell types throughout development, regulating lineage-restricted gene activation and silencing.
Several mechanisms for HMT recruitment to lineage-specific GREs have been described, but there is no clear consensus in the field.
Time-resolved analysis shows that transcription factor binding often precedes histone modification changes in the neighboring nucleosomes.
Lin-TFs can interact with HMT complexes.
Lin-TFs are targets of a large number of modifying enzymes. Some of the resulting PTMs have been reported to modulate interactions of Lin-TFs with other proteins.

Histone methylation is required for the establishment and maintenance of gene expression patterns that determine cellular identity, and its perturbation often leads to aberrant development and disease. Recruitment of histone methyltransferases (HMTs) to gene regulatory elements (GREs) of developmental genes is important for the correct activation and silencing of these genes, but the drivers of this recruitment are largely unknown. Here we propose that lineage-instructive transcription factors (Lin-TFs) act as general recruiters of HMT complexes to cell type-specific GREs through protein–protein interactions. We also postulate that the specificity of these interactions is dictated by Lin-TF post-translational modifications (PTMs), which act as a ‘transcription factor code’ that can determine the directionality of cell fate decisions during differentiation and development.

Section snippets

Recruitment of HMTs: a crucial but anonymous affair

Cells’ ability to acquire new fates is central to the development of multicellular organisms. Cell fate (see Glossary) transitions are triggered by the binding of Lin-TFs to specific sequence motifs in GREs – namely, promoters and enhancers – that orchestrate cell type-specific gene expression programs by activating and silencing cell lineage-restricted genes [1]. In addition, an extra layer of regulation is provided by histone modifications, which modulate chromatin compaction or the binding

Binding of Lin-TFs to GREs precedes histone mark changes

One of the main arguments for the hypothesis that Lin-TFs recruit HMTs is that they are able to force a cell fate switch into other lineages by binding to cell type-specific GREs. For example, overexpression of MyoD in fibroblasts converts them to muscle cells [28], C/EBPα and β can transdifferentiate B lymphocytes into macrophages [29], the combination of Ascl1, Brn2, and Myt1l converts fibroblasts into neurons [30], and the Yamanaka cocktail factors (Oct4, Sox2, Klf4, and Myc) reprograms

Lin-TFs can recruit HMTs to developmentally relevant GREs

Lin-TFs have long been known to directly interact with HATs and recruit them to GREs during the activation of developmental genes. However, there are also reports of an interaction between Lin-TFs and HMTs. For example, C/EBPα has been shown to directly interact with four core components of the TrxG family MLL complex – namely, Wdr5, Ash2l, Dpy30, and Rbbp5 [38,40] – hinting at a more general role for TFs in the recruitment of HMTs to developmentally relevant GREs. Along the same lines, recent

PTMs in Lin-TFs can modulate HMT recruitment

A more recent study on the same system described that histones at the Myf5 enhancer become decorated with H3K4me2/3 only in the daughter cell that activates Myf5 expression. By contrast, the daughter cell that remains a satellite stem cell does not become methylated at the enhancer despite the binding of Pax7. In addition, deposition of H3K4me2/3 in the daughter cell that commits to the muscle lineage occurs only when Pax7 is methylated by Carm1. More specifically, Carm1 methylates four

Lin-TFs harbor a large number of PTMs that can modulate their interaction with other proteins

While it is well known that histone modifications can modulate chromatin dynamics and gene expression, the regulatory functions of PTMs in Lin-TFs are poorly understood. Currently, the best known example of a specific PTM that modulates TF activity is the phosphorylation of specific residues, acting as an on-and-off switch [48,49]. However, the Pax7 example shows that there are additional PTMs that can modulate the interaction of Lin-TFs with other proteins (Figure 2). This raises more general

Concluding remarks

Here we have discussed some examples in which Lin-TFs recruit HMTs. We propose that they directly interact with HMT complex components and recruit them to developmental GREs. In analogy to histones, this interaction does not necessarily have to be unique, in that different Lin-TFs could interact with the same HMT and, vice versa, that different HMTs could interact with a given Lin-TF (Figure 3B, Key figure). We further propose that the specificity of these interactions can be modulated by the

Acknowledgments

The authors thank Achim Leutz, Luciano Di Croce, Tian V. Tian, and Marcos Plana-Carmona for their feedback on the manuscript. We also acknowledge support of the Spanish Ministry of Science and Innovation.

Declaration of interests

The authors declare no interests.

Glossary

Asymmetric division: a cell division that produces two daughter cells with different cellular fates.
Cell fate: a cell’s future phenotypic identity through differentiation or division, determined by intrinsic and extrinsic factors.
Cell lineage: a specific developmental pathway from immature precursors to terminally differentiated cells.
Epigenetic code: the effect of covalent modifications on DNA and adjacent structures (mainly histones) on gene expression. It is a layer of regulation above the genetic

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Trends in Cell Biology

OpinionThe transcription factor code: a beacon for histone methyltransferase docking

Highlights

Section snippets

Recruitment of HMTs: a crucial but anonymous affair

Binding of Lin-TFs to GREs precedes histone mark changes

Lin-TFs can recruit HMTs to developmentally relevant GREs

PTMs in Lin-TFs can modulate HMT recruitment

Lin-TFs harbor a large number of PTMs that can modulate their interaction with other proteins

Concluding remarks

Acknowledgments

Declaration of interests

Glossary

Cell

Cell

Cell

J. Biol. Chem.

Cell

Cell

Mol. Cell

Cell

Cell

Cell

Mol. Cell

Stem Cell Rep.

Mol. Cell

Mol. Cell

Cell Stem Cell

Cell Stem Cell

Curr. Opin. Struct. Biol.

Curr. Opin. Cell Biol.

Cytokine

Immunity

iScience

Trends Cell Biol.

Epigenetic plasticity and the hallmarks of cancer

Science

The language of covalent histone modifications

Nature

Translating the histone code

Science

Histone core modifications regulating nucleosome structure and dynamics

Nat. Rev. Mol. Cell Biol.

Histone acetylation in chromatin structure and transcription

Nature

Roles and regulation of histone methylation in animal development

Nat. Rev. Mol. Cell Biol.

Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation

Nat. Genet.

Opinion
The transcription factor code: a beacon for histone methyltransferase docking