Heterochromatin formation studied widely in fission

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The mechanism of heterochromatin formation and maintenance was extensively dissecting in fission yeast (Saccharomyces pombe), in which three distinct mechanisms have been identified (Lippman and Martienssen 2004; Djupedal et al. 2009; Reyes-Turcu et al. 2011). In all the characterized mechanisms, the heterochomatin formation involves the transcription of PCT sequences by RNA polymerase II (RNApolII) and subsequent PCT transcripts processing into short interfering RNAs (siRNAs), which can involve the RNA interference (RNAi) pathway (Lippman and Martienssen 2004), an alternate RNAi pathway with secondary stem loop structures as triggers (Djupedal et al.

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2009), or an RNAi-independent mechanism that acts in parallel to the RNAi pathway (Reyes-Turcu et al. 2011). The PCT transcripts are a vital component for heterochromatin formation and maintenance, due their role in recruit heterochromatin factors that maintain the heterochromatin modifications, mainly H3K9me2/3 and H3K27me2/3 (Lippman and Martienssen 2004; Chen et al. 2008; Djupedal et al. 2009; Reyes-Turcu et al. 2011). Intriguingly, a paradox was governed at heterochromatic regions: heterochromatin is transcribed to maintain its inactive state.

The heterochromatin establishment at pericentromeres involving similar RNAi machinery has also been identified in other organism, including plants (e.g. rice, maize and Arabidopsis), invertebrates (Drosophila and tammar wallaby) and vertebrates (Fukagawa et al. 2004; Lippman and Martienssen 2004; Neumann et al. 2007; Hsieh et al. 2011). Indeed, the involvement of RNAi in heterochromatin formation in vertebrates as debated in the last years, namely in mouse and human, having some conflicting reports related to transcripts size, cell cycle expression pattern and their involvement in heterochromatin assembly (reviewed in Chan and Wong 2012). Despite the initial difference of opinions (e.

g. Kanellopoulou et al. 2005 vs Murchison et al. 2005), the involvement of Dicer/RNAi analogous pathways has reported in heterochromatin assembly in mouse. The condensation of chromatin might be due to WDHD1 (WD repeat and HMG-box DNA binding protein 1), an acidic nucleoplasmic DNA-binding protein whose activity is coupled to RNAPII transcription, which their association with centromere in mid-to-late S phase plays a role in satellite transcripts processing by a similar pathway to the RNAi pathway Dicer-dependent in yeast (Hsieh et al. 2011). In WDHD1 knock-down experiments the localization of HP1 and epigenetic silencing at (peri)centromeric regions are compromised, leading to an increase in the transcription of both CT and PCT mouse satellites (MiSat and MaSat, referred in Chapter I) and a decrease in the compaction of centromeric heterochomatin, leading a cell cycle abnormalities due the effects in centromere integrity and genomic stability (Hsieh et al. 2011). The involvement of murine non-siRNA-sized PCT transcripts to establishing heterochromatin formation has been reported in several works. In mitotic somatic mouse cells, the transcription of PCT transcripts is cell cycle regulated. Lu and Gilbert (2007) revealed the presence of a heterogeneous population of long PCT transcripts (with 1 kb to more than 8 kb length) in G1, with an increased level in G1/S transition and decrease before the replication of PCT heterochromatin. The presence of these transcripts in the outer surface of the chromocenters (replication of the PCT sequences) suggests that these transcripts can operate in the remodeling of the pericentric chromatin. Moreover, these authors also identified small MaSat transcripts (€ј200 nt) in the early mitosis (Lu and Gilbert 2007). Indeed, the accumulation of PCT transcripts at pericentric regions of condensing chromosomes at the G2/M phase reinforces their role in the remodeling of the heterochromatin structure in the latest mitosis phases or in the maintenance of the centromere structure (Lu and Gilbert 2007; Bulut-Karslioglu et al. 2012). As referred in chapter I, the heterochromatin was characterized by specific epigenetic marks, and their formation in mammals involves the methylation of histone H3 at lysine 9 (H3K9me) by Suv39h (methyltransferases) and subsequent recruitment of chromodomain proteins such as HP1 (Grewal and Jia 2007). The molecular mechanisms how non-coding PCT transcripts initiate and maintain mammalian heterochromatin remain unclear. Howsoever, several studies have been clarifying the binding partners for PCT sequences that, ultimately, are involved in heterochomatinization process, which are characterized by a fine regulation of transcription level. The transcription factors Pax3 and Pax9 are identified as redundant regulators of mouse heterochromatin, as they repress RNA output from major satellite sequences by associating with DNA within PCT heterochromatin (Bulut-Karslioglu et al. 2012). Nevertheless, others transcription factors can be involved in the regulation of PCT transcription, since potential binding sites resides on PCT satellites (e.g. YY1 factor, Shestakova et al. 2004). Maison et al. (2011) demonstrates that mouse long single stranded (ss) PCT transcripts associates with HP1 and this complex is guided at the pericentric heterochromatin domain to seed further HP1 localization. A more recent work by Camacho et al. (2017) propose an RNA-mediated process to govern the stable association of the Suv39h enzymes at mouse heterochromatin (Figure 1), in which MaSat transcripts remain associated to the chromatin and form RNA:DNA hybrids and induce the formation of a higher-order RNA-nucleosome scaffold that would represent the underlying structure of mouse heterochromatin (see in Chapter I the MaSat organization into HORs). Also, in humans, alpha satellite ssPCT transcripts in association with chromatin contribute to the localization of SUV39H1 at constitutive heterochromatin (CH) (Johnson et al. 2017). Although, evidences for HP1 localization through alpha satellite RNA binding has not yet been reported in humans.