A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress

McMurchy, Alicia N.; Stempor, Przemyslaw; Gaarenstroom, Tessa; Wysolmerski, Brian; Yan, Dong; Aussianikava, Darya; Appert, Alex; Huang, Ni; Kolasinska-Zweirz, Paulina; Sapetschnig, Alexandra; Miska, Eric A.; Ahringer, Julie

doi:10.1101/112847

Cited by 21 publications

(40 citation statements)

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“…In both cep-1(RNAi);let-418(n3536) and cep-1(RNAi);chd-3(eh4) worms, we observed a significant reduction in corpses, suggesting that the presence of both Mi2 paralogs is necessary to prevent activation of the DDR/recombination checkpoint ( Figure 1D). These findings also provide a plausible explanation for the increased brood size recently reported in cep-1;let-418 double mutants (McMurchy et al, 2017), which our data indicate is at least in part due to a reduction in germline apoptosis.…”

Section: Activation Of the Recombination/dna Damage Response Checkpoisupporting

confidence: 84%

“…Our findings that ATPase Mi2 promotes timely and accurate repair of DSBs in meiotic nuclei underscores its importance in protecting the germ line and ensuring gamete quality (Figure 7). These data are particularly intriguing in light of recent findings identifying LET-418 as one of several classes of heterochromatin factors required to suppress repetitive elements in both worms and mammals (McMurchy et al, 2017;Montoya-Durango et al, 2016). As CHD4 interacts directly with both checkpoint proteins and HR machinery in human cell lines (Pan et al, 2012;Urquhart et al, 2011), an attractive possibility is that similar functional interactions may take place during meiosis.…”

Section: Discussionmentioning

confidence: 98%

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Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination. We discovered that loss of either CHD-3 or LET-418 results in elevated p53-dependent germline apoptosis, which relies on the activation of the conserved checkpoint kinase CHK-1. Consistent with these findings, chd-3 and let-418 mutants produce a reduced number of offspring, indicating a role for Mi2 in forming viable gametes. When Mi2 function is compromised, persisting recombination intermediates are detected in late pachytene nuclei, indicating a failure in the timely repair of DSBs. Intriguingly, our data indicate that in Mi2 mutant germ lines, a subset of DSBs are repaired by non-homologous end joining, which manifests as chromosomal fusions.We find that meiotic defects are exacerbated in Mi2 mutants lacking CKU-80, as evidenced by increased recombination intermediates, corpses, and defects in chromosomal integrity. Taken together, our findings support a model wherein the C. elegans Mi2 complex maintains genomic integrity through reinforcement of a chromatin landscape suitable for homology-driven repair mechanisms.4

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Section: Activation Of the Recombination/dna Damage Response Checkpoisupporting

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

et al. 2018

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“…Interestingly, germline-specific Argonaute HRDE-1 (heritable RDE1/worm AGO9) along with HP1 ortholog HPL-2 and methyltransferases SET25/SET32 (Fig. 3B) can promote multigenerational inheritance in worm germlines [89,90] Hence, different types of small RNAs transcribed from the repeat-rich regions of the constitutive heterochromatin are essential in maintaining the genomic integrity of the germ cells, making it a common theme across several kingdoms.…”

Section: Role Of Heterochromatic Transcripts In Germline Epigenome Mamentioning

confidence: 99%

Heterochromatic hues of transcription—the diverse roles of noncoding transcripts from constitutive heterochromatin

Saha

Mishra

2019

The FEBS Journal

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Constitutive heterochromatin has been canonically considered as transcriptionally inert chromosomal regions, which silences the repeats and transposable elements (TEs), to preserve genomic integrity. However, several studies from the last few decades show that centromeric and pericentromeric regions also get transcribed and these transcripts are involved in multiple cellular processes. Regulation of such spatially and temporally controlled transcription and their relevance to heterochromatin function have emerged as an active area of research in chromatin biology. Here, we review the myriad of roles of noncoding transcripts from the constitutive heterochromatin in the establishment and maintenance of heterochromatin, kinetochore assembly, germline epigenome maintenance, early development, and diseases. Contrary to general expectations, there are active protein‐coding genes in the heterochromatin although the regulatory mechanisms of their expression are largely unknown. We propose plausible hypotheses to explain heterochromatic gene expression using Drosophila melanogaster as a model, and discuss the evolutionary significance of these transcripts in the context of Drosophilid speciation. Such analyses offer insights into the regulatory pathways and functions of heterochromatic transcripts which open new avenues for further investigation.

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“…Growth at 25ºC, instead of the standard condition of 20ºC, resulted in increased levels of RNA from some transposons (70). Given the importance of silencing transposons and maintaining genome integrity, it is not surprising that multiple small RNA and chromatin remodeling pathways act to prevent the mobilization of repetitive elements under normal and stress conditions (70,71). Nonetheless, the up-regulation of RNAs from multiple repeat families during HS indicates that these silencing pathways become compromised in harsh environments.…”

Section: Specific Ncrnas From Multiple Classes Respond To Heat Shockmentioning

confidence: 99%

Remodeling of theC. elegansNon-coding RNA Transcriptome by Heat Shock

Schreiner¹,

Pagliuso²,

Garrigues³

et al. 2019

Preprint

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Elevated temperatures activate a Heat Shock Response (HSR) to protect cells from the pathological effects of protein mis-folding, cellular mis-organization, organelle dysfunction and altered membrane fluidity. This response includes activation of the conserved transcription factor Heat Shock Factor 1 (HSF-1), which binds Heat Shock Elements (HSEs) in the promoters of genes induced by heat shock (HS). The upregulation of protein-coding genes (PCGs), such as Heat Shock Proteins (HSPs) and cytoskeletal regulators, is critical for cellular survival during elevated temperatures. While the transcriptional response of PCGs to heat shock has been comprehensively analyzed in a variety of organisms, the effect of this stress on the expression of noncoding RNAs (ncRNAs) has not been systematically examined. Here we show that in Caenorhabditis elegans HS induces up-and down-regulation of specific ncRNAs from multiple classes, including miRNA, piRNA, lincRNA, pseudogene, and repeat elements. Moreover, some ncRNA genes appear to be direct targets of the HSR, as they contain HSF-1 bound HSEs in their promoters and their expression is regulated by this factor during HS. These results demonstrate that multiple ncRNA genes respond to HS, some as direct HSF-1 targets, providing new candidates that may contribute to organismal survival during this stress.

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A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress

Cited by 21 publications

References 100 publications

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

Heterochromatic hues of transcription—the diverse roles of noncoding transcripts from constitutive heterochromatin

Remodeling of theC. elegansNon-coding RNA Transcriptome by Heat Shock

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