Review Article | Published:

Ten principles of heterochromatin formation and function

Nature Reviews Molecular Cell Biology volume 19, pages 229244 (2018) | Download Citation

Abstract

Heterochromatin is a key architectural feature of eukaryotic chromosomes, which endows particular genomic domains with specific functional properties. The capacity of heterochromatin to restrain the activity of mobile elements, isolate DNA repair in repetitive regions and ensure accurate chromosome segregation is crucial for maintaining genomic stability. Nucleosomes at heterochromatin regions display histone post-translational modifications that contribute to developmental regulation by restricting lineage-specific gene expression. The mechanisms of heterochromatin establishment and of heterochromatin maintenance are separable and involve the ability of sequence-specific factors bound to nascent transcripts to recruit chromatin-modifying enzymes. Heterochromatin can spread along the chromatin from nucleation sites. The propensity of heterochromatin to promote its own spreading and inheritance is counteracted by inhibitory factors. Because of its importance for chromosome function, heterochromatin has key roles in the pathogenesis of various human diseases. In this Review, we discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms.

Key points

  • Protein domains that bind ('read') histones bearing specific post-translational modifications are frequently physically coupled to enzymes that catalyse the addition ('writer') or removal ('eraser') of histone modifications.

  • Transcription of heterochromatin produces noncoding RNAs that provide recruitment platforms for chromatin-modifying enzymes.

  • The processes that initiate heterochromatin establishment are separable from those that mediate its maintenance. Once initiated, heterochromatin can engulf neighbouring chromatin, but spreading is limited by multiple mechanisms.

  • Reader–writer coupling suggests that heterochromatin can direct its persistence through replication and cell division independently of nucleic acid cues. Experimental tests suggest that heterochromatin heritability is strongly countered by opposing activities.

  • Heterochromatin suppresses chromosome rearrangements by directing specific avenues of repair within repetitive DNA. Heterochromatin also promotes accurate chromosome segregation.

  • Domains of heterochromatin limit the repertoire of expressed genes in differentiated cells and inhibit their reprogramming to pluripotent cells. A variety of human diseases are affected by the alterations in the ability to form, or the distribution of, heterochromatin.

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Acknowledgements

R.C.A. is a Wellcome Principal Research Fellow; his research is supported by the UK Wellcome Trust (200885) and core funding of the UK Wellcome Centre for Cell Biology (203149). Research in the laboratory of H.D.M. is supported by grants from the US National Institutes of Health. H.D.M. is a Chan-Zuckerberg BioHub investigator. The authors apologize to colleagues whose work could not be cited because of length restrictions. The authors dedicate this piece to the memory of A. Klar, whose pioneering studies of cell-type specification and gene silencing in Saccharomyces cerevisiae and Schizosaccharomyces pombe paved the way for many advances.

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Affiliations

  1. Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.

    • Robin C. Allshire
  2. Chan-Zuckerberg BioHub, San Francisco, California 94158, USA.

    • Hiten D. Madhani
  3. Department of Biochemistry and Biophysics, University of California–San Francisco, California 95158, USA.

    • Hiten D. Madhani

Authors

  1. Search for Robin C. Allshire in:

  2. Search for Hiten D. Madhani in:

Contributions

R.C.A. and H.D.M. each researched data for the article, made substantial contributions to the discussion of content, wrote the manuscript and reviewed and edited it before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Robin C. Allshire or Hiten D. Madhani.

Glossary

Post-translational modifications

(PTMs). Chemical groups (such as methyl or acetyl) on amino acid side chains that are enzymatically added by 'writer', removed by 'eraser' and recognized by 'reader' protein modules.

Satellite repeats

Short repetitive sequences that exhibit a distinct satellite peak on buoyant density gradients owing to their skewed base composition.

Constitutive heterochromatin

In most eukaryotes, heterochromatin that is consistently formed throughout the cell cycle and in many cell types, for example, centrome-reassociated heterochromatin.

Facultative heterochromatin

Locus-specific and cell-type-specific heterochromatin, for example, the inactive X chromosome in mammals.

Chromoshadow domain

(CSD). Dimerization domain in heterochromatin protein 1-related proteins that forms a peptide-binding groove at the dimer interface that can recruit additional heterochromatin proteins.

Argonaute

Proteins with PAZ and Piwi domains that are loaded with small RNAs, which target them and their associated proteins to long RNAs that bear homology to the small RNA.

Pericentromeric heterochromatin

Large blocks of heterochromatin formed on the tandem repeats that surround the centromere–kinetochore region.

X chromosome inactivation

Mechanism of dosage compensation in female mammals in which one of the two X chromosomes is inactivated by the formation of facultative heterochromatin.

X-inactive specific transcript

(XIST). Long noncoding RNA that designates the X chromosome from which it is expressed for X chromosome inactivation.

Piwi-associated RNAs

(piRNAs). Small RNAs associated with Piwi members of the Argonaute protein superfamily, which promotes repression of transposable elements in animal gonads.

R-loops

Nascent RNA that remains associated with its DNA template through hybridization, thereby dislodging the opposite, nontemplate DNA strand.

Heterochromatin islands

Extensive domains of heterochromatin on chromosome arms, which are distinct from the main centromeric and telomeric heterochromatin domains.

Reprogramming-resistant regions

Large lineage-specific chromosomal regions that are assembled into heterochromatin and thus resist binding by reprogramming factors.

Endogenous retroelements

Mobile elements that replicate through reverse transcription followed by genomic integration. The term also includes degenerate, immobile elements.

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DOI

https://doi.org/10.1038/nrm.2017.119

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