The C. elegans SET-2/SET1 histone H3 Lys4 (H3K4) methyltransferase preserves genome stability in the germline

Herbette, Marion; Mercier, Marine; Michal, Fanny; Cluet, David; Burny, Claire; Yvert, Gaël; Robert, Valérie; Palladino, Francesca

doi:10.1016/j.dnarep.2017.07.007

Cited by 36 publications

(35 citation statements)

References 91 publications

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“…The following antibodies were used: DDX17 proteins (ab71958, Abcam), DDX5 (Pab204, Millipore) and REST (07-579, Millipore). Quantification of the PLA foci was based on a previously described macro (45) that was optimized to detect foci within nuclei of human cells. The macro was designed to automatically detect and process batches of microscope-coupled acquisitions, as detailed in Supplementary Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

Lambert

Terrone

Giraud

et al. 2018

Nucleic Acids Research

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The Repressor Element 1-silencing transcription factor (REST) represses a number of neuronal genes in non-neuronal cells or in undifferentiated neural progenitors. Here, we report that the DEAD box RNA helicase DDX17 controls important REST-related processes that are critical during the early phases of neuronal differentiation. First, DDX17 associates with REST, promotes its binding to the promoter of a subset of REST-targeted genes and co-regulates REST transcriptional repression activity. During neuronal differentiation, we observed a downregulation of DDX17 along with that of the REST complex that contributes to the activation of neuronal genes. Second, DDX17 and its paralog DDX5 regulate the expression of several proneural microRNAs that are known to target the REST complex during neurogenesis, including miR-26a/b that are also direct regulators of DDX17 expression. In this context, we propose a new mechanism by which RNA helicases can control the biogenesis of intronic miRNAs. We show that the processing of the miR-26a2 precursor is dependent on RNA helicases, owing to an intronic regulatory region that negatively impacts on both miRNA processing and splicing of its host intron. Our work places DDX17 in the heart of a pathway involving REST and miRNAs that allows neuronal gene repression.

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Section: Methodsmentioning

confidence: 99%

The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

Lambert

Terrone

Giraud

et al. 2018

Nucleic Acids Research

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“…Likewise, increased genome instability in set-2 mutant germlines was not associated with defects in the induction of the DNA damage response (DDR) pathway, consistent with downstream effects in the DNA repair process (Herbette et al, 2017). Together, these recent observations suggest that SET-2 may play roles in modifying chromatin structure independently of specific changes in gene expression.…”

Section: Introductionmentioning

confidence: 73%

“…Proper chromatin organization is required for chromosome segregation, and its disruption can result in chromosome segregation defects in mitosis and meiosis (Potapova & Gorbsky, 2017). These defects were not found in set-2 mutant germlines or embryos at any of the temperatures tested (Beurton et al, 2019;Herbette et al, 2017). However, at the permissive temperature (20°C), endoreplicated intestinal cells of adult animals showed chromosome segregation defects very similar to those reported in condensin-II mutants (Csankovszki et al, 2009).…”

Section: Knock-downmentioning

confidence: 99%

“…Inactivation of set-2, the single SET1 homolog in C. elegans, results in defective patterns of H3K4me3 in the germline, progressive misregulation of the germline transcriptome, increased genome instability, and loss of germ cell identity leading to sterility (Herbette et al, 2017;Li & Kelly, 2011;Robert et al, 2014;Xiao et al, 2011). Whether these defects reflect a direct role of SET-2 in transcription, or a more general role in germline chromatin organization is not known.…”

Section: Introductionmentioning

confidence: 99%

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Cooperation between Caenorhabditis elegansCOMPASS and condensin in germline chromatin organization

Herbette

Robert

Bailly

et al. 2020

Preprint

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Deposition of histone H3 lysine 4 (H3K4) methylation at promoters by SET1/COMPASS is associated with context-dependent effects on gene expression and local changes in chromatin organization.Whether SET1/COMPASS also contributes to higher-order chromosome structure has not been investigated. Here, we address this question by quantitative FRET (Förster resonance energy transfer)based fluorescence lifetime imaging microscopy (FLIM) on C. elegans germ cells expressing histones H2B-eGFP and H2B-mCherry. We find that SET1/COMPASS subunits strongly influence meiotic chromosome organization, with marked effects on the close proximity between nucleosomes. We further show that inactivation of SET-2, the C. elegans homologue of SET1, or CFP-1, the chromatin targeting subunit of COMPASS, strongly enhance chromosome organization defects and loss of fertility resulting from depletion of condensin-II. Defects in chromosome morphology resulting from conditional inactivation of topoisomerase II, another structural component of chromosomes, were also aggravated in the absence of SET-2. Combined, our in vivo findings suggest a model in which the SET1/COMPASS histone methyltransferase complex plays a role in shaping meiotic chromosome in cooperation with the non-histone proteins condensin-II and topoisomerase.

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“…Nematode strain maintenance was described previously (Brenner 1974). The strain set-2(bn129) III/qC1(qIs26) used in this study is described in (Herbette et al 2017).…”

Section: Strains and Maintenancementioning

confidence: 99%

TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

Robert

Knutson

Rechtsteiner

et al. 2019

Preprint

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Chromatin factors contribute to germline maintenance by preserving a germline-appropriate transcriptional program. In the absence of the conserved histone H3 Lys4 (H3K4) methyltransferase SET-2, C. elegans germ cells progressively lose their identity over generations, leading to sterility. How this transgenerational loss of fertility results from the absence of SET-2 is unknown. Here we performed expression profiling across generations on germlines from mutant animals lacking SET-2 activity. We found that gene deregulation occurred in 2 steps: a priming step in early generations progressing to loss of fertility in later generations. By performing Within-Class Analysis (WCA), a derivative of Principal Component Analysis, we identified transcriptional signatures associated with SET-2 inactivation, both at the priming step and later on during loss of fertility. Further analysis showed that repression of germline genes, derepression of somatic programs, and X-chromosome desilencing through interference with PRC2-dependent repression, are priming events driving loss of germline identity in the absence of SET-2. Decreasing expression of identified priming genes, including the C/EBP homologue cebp-1 and TGF- pathway components, was sufficient to delay the onset of sterility, suggesting that they individually contribute to the loss of germ cell fate. Altogether, our findings illustrate how the loss of a chromatin regulator at one generation can progressively deregulate multiple transcriptional and signaling programs, ultimately leading to loss of appropriate cell fate.

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The C. elegans SET-2/SET1 histone H3 Lys4 (H3K4) methyltransferase preserves genome stability in the germline

Cited by 36 publications

References 91 publications

The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

Cooperation between Caenorhabditis elegansCOMPASS and condensin in germline chromatin organization

TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

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