The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease

doi:10.1016/j.tig.2019.06.004

Trends in Genetics

Volume 35, Issue 9, September 2019, Pages 645-657

https://doi.org/10.1016/j.tig.2019.06.004 Get rights and content

Highlights

An abundance of recent findings suggest that, surprisingly, numerous epigenetic regulators also possess an array of critical noncatalytic roles in addition to their canonical histone modifying enzymatic activities.
These functions range from the recruitment of other epigenetic modifiers and critical transcription factors to unexpected cytoplasmic functions and roles in three-dimensional genome organization, together offering extensive new insights into epigenome function and gene regulation.
These discoveries reveal how the aberrant function of these epigenetic modifiers leads to profoundly altered transcriptional landscapes, ultimately disrupting developmental programs or driving carcinogenesis.
Collectively, these mechanistic insights are providing exciting rationale for the testing of novel epigenome-targeting therapies in order to harness the tremendous potential of epigenetic therapy for human disease.

Epigenetic regulation is critical for the precise control of cellular fate and developmental programs. Disruption of epigenetic information is increasingly appreciated as a potential driving mechanism in both developmental disorders as well as ubiquitous diseases such as cancer. Consistent with this, mutations in histone modifying enzymes are amongst the most frequent events in all of human cancer. While early studies have focused on the canonical enzymatic functions involved in catalyzing modifications to histones, more recent studies have uncovered a new layer of critical nonenzymatic roles in transcriptional regulation for these proteins. Here, we provide an overview of these surprising, yet exciting, noncanonical, noncatalytic roles, and highlight how these revelations may have important implications for understanding disease and the future of epigenome-targeting therapies.

Section snippets

Histone Modifiers in the Establishment and Maintenance of Cellular Fate and Identity

Dynamic epigenetic (see Glossary) regulation is dictated by the intricate organization of each cell’s genome into chromatin. The fundamental unit of chromatin is the nucleosome, and the compaction of chromatin has a profound influence on gene expression levels, with more open regions (euchromatin) tending to be transcriptionally active, while more compacted regions (heterochromatin) tend to be transcriptionally repressed [1]. Histone post-translational modifications are able to orchestrate

All En-COMPASS-ing Regulation at Enhancers and Promoters

Methylation on histone 3 lysine 4 (H3K4) marks actively transcribed genes and their enhancers and promoters during cellular development, differentiation, and homeostasis [15]. From flies to humans, these modifications are highly conserved and catalyzed by family members of a macromolecular epigenetic machine known as COMPASS (complex of proteins associated with Set 1) [15] (Box 2). Investigations into COMPASS enzymes and how they may play a role in disease have provided significant rationale

Polycomb Complexes: Marking the Balance between Development, Differentiation, and Cancer

Opposing the canonical transcriptional activating abilities of the COMPASS complex is the polycomb repressive complex [28]. This dynamic repression system is marked typically by trimethylation of histone H3K27, which is mediated by polycomb repressive complex 2 (PRC2). The core PRC2 is composed of the SET-domain containing methyltransferase enhancer of zeste 2 (EZH2/KMT6A) or its closely related homolog EZH1 (KMT6B) and also comprises the core subunits suppressor of zeste 12 (SUZ12) and

Concluding Remarks

This collective body of recent studies highlights the multiple, diverse, and essential noncatalytic functions of several histone modifier families during proper cellular development, homeostasis, differentiation, and disease. While we were not able to address the potential noncatalytic roles of all histone modifiers here due to limitations of space, we believe the studies highlighted here are highly representative and serve as a great framework from which to consider all chromatin regulators.

Acknowledgments

We apologize to those whose work could not be included in this review article, owing to space limitations. The B.C.C. laboratory is funded by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health under Award Number K08AR070289, the Damon Runyon Cancer Foundation, the Dermatology Foundation, and the Penn Skin Biology and Diseases Resource-based Center, funded by NIAMS 1P30AR069589-01.

Glossary

BAF (SWI/SNF) chromatin remodeling complex: BRG1/BRM associated factor (BAF) is one of the four mammalian ATP-dependent chromatin-remodeling complexes. In humans, this 2-MDa protein complex contains up to 15 subunits, including BAF250a/b, BRG1/BRM, BAF155/170, BAF60, BAF53, BAF47, and BAF45. Mechanistically, the BAF chromatin remodeling complex contributes to chromatin remodeling by hydrolyzing ATP, which generates energy for nucleosomal unwrapping, mobilization, ejection, or histone dimer

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⁵: Laboratory website: https://www.med.upenn.edu/capelllab/.

⁶: These authors contributed equally to this work.

^@: Twitter: @briancapell (B.C. Capell).

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Trends in Genetics

ReviewThe Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease

Highlights

Section snippets

Histone Modifiers in the Establishment and Maintenance of Cellular Fate and Identity

All En-COMPASS-ing Regulation at Enhancers and Promoters

Polycomb Complexes: Marking the Balance between Development, Differentiation, and Cancer

Concluding Remarks

Acknowledgments

Glossary

Cell

J. Biol. Chem.

Cancer Cell

Nat. Med.

Cell Rep.

Mol. Cell

Cancer Cell

Mol. Cell

Mol. Cell

Eur. J. Cancer

Curr. Opin. Genet. Dev.

Mol. Cell

Cell

Am. J. Hum. Genet.

The molecular hallmarks of epigenetic control

Nat. Rev. Genet.

Characterization of individual histone posttranslational modifications and their combinatorial patterns by mass spectrometry-based proteomics strategies

Methods Mol. Biol.

A chemical probe toolbox for dissecting the cancer epigenome

Nat. Rev. Cancer

The interplay of epigenetic marks during stem cell differentiation and development

Nat. Rev. Genet.

The role of enhancers in cancer

Nat. Rev. Cancer

Cell-of-origin chromatin organization shapes the mutational landscape of cancer

Nature

Epigenetic control of adult stem cell function

Nat. Rev. Mol. Cell Biol.

Cancer stem cells: an evolving concept

Nat. Rev. Cancer

Unravelling cancer stem cell potential

Nat. Rev. Cancer

DNA methylation and DNA methyltransferases

Epigenetics Chromatin

Functions and mechanisms of non-histone protein acetylation

Nat. Rev. Mol. Cell Biol.

50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond

Nat. Rev. Mol. Cell Biol.

The DNA methyltransferase family: a versatile toolkit for epigenetic regulation

Nat. Rev. Genet.

The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis

Annu. Rev. Biochem.

The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers

Mol. Cell. Biol.

H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation

eLife

Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis

Proc. Natl. Acad. Sci. U. S. A.

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Proc. Natl. Acad. Sci. U. S. A.

KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis

Genes Dev.

Histone H3K27ac separates active from poised enhancers and predicts developmental state

Proc. Natl. Acad. Sci. U. S. A.

MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis

Nucleic Acids Res.

Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation

Mol. Cell

Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

Nat. Genet.

A UTX-MLL4-p300 transcriptional regulatory network coordinately shapes active enhancer landscapes for eliciting transcription

Mol. Cell

Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers

Cell Res.

Identification of H3K4me1-associated proteins at mammalian enhancers

Nat. Genet.

Epigenetic balance of gene expression by Polycomb and COMPASS families

Science

UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development

Nature

Review
The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease