Suv39h1 links the SUMO pathway to constitutive heterochromatin

Abstract

The Suv39h lysine methyltransferases, known as key enzymes responsible for histone H3 lysine 9 methylation, are critical for heterochromatin protein 1 enrichment at constitutive heterochromatin. Our recent findings reveal a new role for the Suv39h1 paralog that links it to SUMO pathway function at constitutive heterochromatin. KEYWORDSHeterochromatin; HP1; nuclear organization; SUMO pathway; suv39h1Heterochromatin has long been considered an inert part of the genome, merely gathering repetitive sequences. The last 10 y of research in chromatin and epigenetics have highlighted the importance of heterochromatin features for transcriptional regulation, nuclear organization, and genomic stability in a variety of species. In particular, histone marks characteristic of constitutive heterochromatin such as histone H3 lysine 9 methylation (H3K9me3) established by distinct "writers" (i.e., the Suv39h lysine methyltransferases [KMTs] in mammals) that protein "readers" (such as heterochromatin protein 1 [HP1]) can recognize provide a paradigm for a mechanism involved in and/or associated with a plethora of genomic functions affecting cell physiology and homeostasis. Notably, these functions include global genomic stability/heritability over cellular division, with a key role at the centromere and telomeres, developmental programs and cell fate, aging and senescence, and cancer. 1-4 Whether these functions originate from the same or distinct features of constitutive heterochromatin, such as solely transcriptional repression or nuclear organization, remains to be documented. It therefore became of the utmost importance to decipher how the dynamics of heterochromatin organization are controlled and how they can be linked to changes in cellular functions during development and most critically in the context of human health. A logical approach has been to focus on the already well-identified players Suv39h, H3K9me3, and HP1 that contribute to various levels of heterochromatin organization. The Suv39h KMTs 5 ensure H3K9me3 marks at nucleosomes in heterochromatin, which in turn provide binding/anchoring sites for the HP1 proteins; the capacity of Suv39h to bind HP1 further contributes to propagation of methylation of H3K9 on neighboring nucleosomes. Once an initiating site has been established, this latter "self-sustaining" loop provides a simple maintenance system for constitutive heterochromatin at specific genomic loci. 6 Using the constitutive heterochromatin at pericentric domains (chromosomal domains flanking the microtubule attachment sites of the sister chromatids during mitosis) in mouse cells as a model, our previous studies showed that the SUMO pathway is involved in the initiation of this loop. We identified that the HP1a isoform was targeted at these domains when post-translationally modified by sumoylation, even in the absence of Suv39h-dependent H3K9me3. Importantly, we revealed a specific interaction between SUMO-HP1a and pericentric RNA transcripts 7 (Fig. 1). Interestingly, in addition to sumoylation, d...

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells

“…The observations that modified ERα was detected as early as 20 min, i.e., before the peak of binding to DNA, and was found in both the chromatin-bound and the nuclear matrix fractions in MCF-7 cells at 1 h [24], are compatible with SUMOylated ERα being associated to DNA. SUMOylation of several general TFs or enhancer factors, including nuclear receptors, was previously reported to take place on DNA [49, 50] and to be associated with transcriptional repression [45, 46, 48, 51–55]. Accordingly, SUMO2/3 ChIP-Seq peaks were enriched in different transcription factor-binding sites, especially CTCF motifs.…”

The control of gene expression and cell identity by H3K9 trimethylation

“…SUMOylation is also implicated in several aspects of heterochromatin formation in different genomic contexts in mammals. Studies in murine cell lines have shown that SUMOylation of HP1α regulates its de novo localization to pericentric chromatin, with Suv39h1 acting as a SUMO E3 ligase (Maison et al, 2011(Maison et al, , 2016. SUMOylation of the core histone H4 induces HP1γ recruitment and local silencing in human cell lines (Shiio and Eisenman, 2003).…”

How HP1 Post-Translational Modifications Regulate Heterochromatin Formation and Maintenance

“…Several studies have shown the implication of SUMO proteins in transcription repression regulation and maintenance of silenced heterochromatin [63]. HP1α can be SUMOylated at the hinge domain by SUMO1, which is crucial for its targeting to pericentric heterochromatin in mice [45]; the methyltransferase Su(var)39H1, but not Su(var)39H2, seems to enhance this SUMOylation [64]. Following HP1α deposition at the pericentric heterochromatin, HP1α SUMOylation is rapidly reversed by SENP7, necessary to stabilize and maintain its binding to chromatin [65].…”