Trends in Genetics
Volume 30, Issue 3, March 2014, Pages 103-110
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Review
HP1a: a structural chromosomal protein regulating transcription

https://doi.org/10.1016/j.tig.2014.01.002Get rights and content

Highlights

  • We propose a structure-based definition of HP1 family proteins.

  • We review evidence that shows HP1 to be a context-dependent modifier of gene expression.

  • Post-translational modifications of HP1 family proteins alter functionality.

Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as ‘hub proteins,’ able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and gene silencing, utilizing a variety of mechanisms. Clearly, HP1 function is altered by context, and potentially by post-translational modifications (PTMs). Here, we report on recent ideas as to how this versatile protein accomplishes its diverse functions.

Section snippets

The versatile HP1 family proteins

HP1a was initially identified as a protein predominantly associated with heterochromatin in a study using immunofluorescent staining of the polytene chromosomes of Drosophila, screening monoclonal antibodies prepared against a collection of tight-binding nuclear proteins [1]. The gene encoding HP1a was first identified in mutagenesis screens for dominant suppressors of heterochromatic position effect variegation (PEV; reviewed in [2]). These and subsequent studies implicated HP1a in PEV, the

The role of HP1a in silencing

A major role of HP1a is in the assembly and maintenance of heterochromatin, a relatively condensed form of chromatin that promotes gene silencing. Indeed, formation of heterochromatin may be an ancient defense designed to silence transposable elements (TEs), which can otherwise wreak havoc in the genome (summarized in [22]). The most detailed evidence for the role of HP1 family proteins in controlling heterochromatin transcription comes from studies in fission yeast. Schizosaccharomyces pombe

The role of HP1a in gene activation

Although HP1a is prominently associated with silencing, there is growing evidence that it can also promote gene expression. HP1a dosage can impact the expression of subsets of genes residing in euchromatin, as well as affecting heterochromatic gene expression (reviewed in [51]). How can a protein that has a major role in silencing also promote gene activation? No doubt the versatility of HP1a in binding to a variety of effector proteins is critical (reviewed in [52]). In addition, HP1 family

HP1 post-translational modifications and chromatin assembly

The stable epigenetic silencing associated with HP1-enriched heterochromatin contrasts with the remarkably dynamic chromatin-binding behavior of mammalian HP1 family proteins (Box 2). Such dynamic behavior may be regulated by PTMs, which could tip the balance towards or away from heterochromatin assembly. Recent systematic mass spectrometry analysis has disclosed evidence for a variety of PTMs of mammalian HP1 family proteins, reminiscent of the histone code [62]. These include phosphorylation,

Concluding remarks

HP1, a small protein with three major domains (CD, H, and CSD), is remarkably influential in promoting distinct forms of packaging within eukaryotic genomes, impacting expression of the genes within those chromatin regions. Although not universal among eukaryotes, the HP1a/H3K9me2/3 silencing mechanism is common and highly conserved in Metazoa. Despite exciting progress during the past decade, much remains to be learned about how HP1 is selectively targeted for heterochromatin formation, how

Acknowledgments

We apologize to the many workers in the field whose papers could not be cited directly due to space limitations. Work in the Elgin lab is supported by NSF grant MCB-1243724. We thank our modENCODE colleagues and members of the Elgin lab for thoughtful comments on the manuscript.

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      We posit that this repressive effect is the result of passive exclusion of RNA polymerase and transcriptional machinery due to steric effects of HP1α polymerization rather than the active epigenetic silencing of the assayed genes. The distinction between active and passive gene repression by HP1α has been proposed previously and may represent divergent consequences of HP1 binding to histone modification-sensitive regulatory elements in euchromatin versus polymerization-permissive, highly repetitive regions in constitutive heterochromatin (Eissenberg and Elgin, 2014; Hediger and Gasser, 2006). We present two lines of evidence in support for a passive mechanism of repression at Chr3q29.

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