Methylation of the glucocorticoid receptor gene (NR3C1) in dyads mother-child exposed to intimate partner violence in Cameroon: Association with anxiety symptoms

Background: The glucocorticoid receptor (GR), which is encoded by the NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1) gene plays an important role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis activity by providing feedback regulation which allows termination of the stress response. Little is known about epigenetic programming at the level of NGFI-A (nerve growth factor-inducible protein A) putative binding site (CpG) of the NR3C1 exon 1F in dyads mother-child exposed to intimate partner violence (IPV) more specifically in an unstudied region such as the sub-Saharan Africa where levels of violence are very high. Objective: Examine NR3C1 exon 1F methylation in response to IPV and possible association with cortisol concentration and mental health. Method: We recruited 20 mother-child dyads exposed to IPV and a control group of 20 mother-child dyads not exposed to IPV. We administered self-reported questionnaires to measure mother's mental health and collected saliva samples for cortisol dosage and bisulfite sequencing of DNA methylation. Results: Regarding the mothers, our results showed a significant difference in methylation level at CpG 16-21 sites of the NR3C1 exon 1F promoter region between the groups. In the exposed group as compared to the control group, there was a significant positive association between the level of methylation at CpG 16-21 sites and mother's mental health in particular anxiety symptoms. However, we did not find any significant correlation between methylation level and cortisol concentration. In children, we did not find any significant results. Conclusion: This study highlights a NGFI-A putative binding site (CpG 16-21) that is more methylated in mothers exposed to IPV and which may have the potential to confer vulnerability for psychopathologies

LET-418/Mi2 and SPR-5/LSD1 cooperatively prevent somatic reprogramming of C. elegans germline stem cells

Throughout their journey to forming new individuals, germline stem cells must remain totipotent, particularly by maintaining a specific chromatin structure. However, the place epigenetic factors occupy in this process remains elusive. So far, “sensitization” of chromatin by modulation of histone arrangement and/or content was believed to facilitate transcription-factor-induced germ cell reprogramming. Here, we demonstrate that the combined reduction of two epigenetic factors suffices to reprogram C. elegans germ cells. The histone H3K4 demethylase SPR-5/LSD1 and the chromatin remodeler LET-418/Mi2 function together in an early process to maintain germ cell status and act as a barrier to block precocious differentiation. This epigenetic barrier is capable of limiting COMPASS-mediated H3K4 methylation, because elevated H3K4me3 levels correlate with germ cell reprogramming in spr-5; let-418 mutants. Interestingly, germ cells deficient for spr-5 and let-418 mainly reprogram as neurons, suggesting that neuronal fate might be the first to be derepressed in early embryogenesis

Specific NuRD components are required for fin regeneration in zebrafish

Background: epimorphic regeneration of a missing appendage in fish and urodele amphibians involves the creation of a blastema, a heterogeneous pool of progenitor cells underneath the wound epidermis. Current evidence indicates that the blastema arises by dedifferentiation of stump tissues in the vicinity of the amputation. In response to tissue loss, silenced developmental programs are reactivated to form a near-perfect copy of the missing body part. However, the importance of chromatin regulation during epimorphic regeneration remains poorly understood.Results: we found that specific components of the Nucleosome Remodeling and Deacetylase complex (NuRD) are required for fin regeneration in zebrafish. Transcripts of the chromatin remodeler chd4a/Mi-2, the histone deacetylase hdac1/HDAC1/2, the retinoblastoma-binding protein rbb4/RBBP4/7, and the metastasis-associated antigen mta2/MTA were specifically co-induced in the blastema during adult and embryonic fin regeneration, and these transcripts displayed a similar spatial and temporal expression patterns. In addition, chemical inhibition of Hdac1 and morpholino-mediated knockdown of chd4a, mta2, and rbb4 impaired regenerative outgrowth, resulting in reduction in blastema cell proliferation and in differentiation defects.Conclusion: altogether, our data suggest that specialized NuRD components are induced in the blastema during fin regeneration and are involved in blastema cell proliferation and redifferentiation of osteoblast precursor cells. These results provide in vivo evidence for the involvement of key epigenetic factors in the cellular reprogramming processes occurring during epimorphic regeneration in zebrafish

Fine-tuning of chromatin composition and Polycomb recruitment by two Mi2 homologues during C. elegans early embryonic development

The nucleosome remodeling and deacetylase complex promotes cell fate decisions throughout embryonic development. Its core enzymatic subunit, the SNF2-like ATPase and Helicase Mi2, is well conserved throughout the eukaryotic kingdom and can be found in multiple and highly homologous copies in all vertebrates and some invertebrates. However, the reasons for such duplications and their implications for embryonic development are unknown.Results: Here we studied the two C. elegans Mi2 homologues, LET-418 and CHD-3, which displayed redundant activities during early embryonic development. At the transcriptional level, these two Mi2 homologues redundantly repressed the expression of a large gene population. We found that LET- 418 physically accumulated at TSS-proximal regions on transcriptionally active genomic targets involved in growth and development. Moreover, LET-418 acted redundantly with CHD-3 to block H3K4me3 deposition at these genes. Our study also revealed that LET-418 was partially responsible for recruiting Polycomb to chromatin and for promoting H3K27me3 deposition. Surprisingly, CHD-3 displayed opposite activities on Polycomb, as it was capable of moderating its LET-418-dependent recruitment and restricted the amount of H3K27me3 on the studied target genes.Conclusion: Although closely homologous, LET-418 and CHD-3 showed both redundant and opposite functions in modulating the chromatin environment at developmental target genes. We identified the interplay between LET-418 and CHD-3 to finely tune the levels of histone marks at developmental target genes. More than just repressors, Mi2-containing complexes appear as subtle modulators of gene expression throughout development. The study of such molecular variations in vertebrate Mi2 counterparts might provide crucial insights to our understanding of the epigenetic control of early development

HPA-axis activity and the moderating effect of self-esteem in the context of intimate partner violence in Cameroon

Background The experience of intimate partner violence (IPV) is stressful. One objective way to monitor it is to assess victims’ stress response by measuring the concentration of their salivary cortisol, the major stress hormone released by the hypothalamic–pituitary–adrenal axis. Objective We investigated how the IPV experienced by women in Cameroon affects their stress levels and those of their children. Method We recruited 50 mother–child dyads exposed to IPV and a control group of 25 mother–child dyads. All mothers completed questionnaires, including the Revised Conflict Tactics Scale to assess IPV, the Sense of Coherence Scale, and the Self-Esteem Scale, to assess their psychological resources. Mothers were asked to collect 3 saliva samples from themselves and 3 from their children on a single weekday: immediately after waking up, 30 minutes after waking up, and 45 minutes after waking up. The total cortisol secretion over the first hour after awakening was determined by calculating the area under the curve with respect to the ground (AUCg). Results Mothers exposed to IPV exhibited higher total post-awakening cortisol concentrations compared with those in the control group. However, no significant difference was found between exposed and non-exposed children. In addition, higher IPV, specifically injuries, was significantly and positively associated with greater AUCg among mothers exhibiting lower self-esteem. When self-esteem was high, however, no significant effect of IPV on AUCg was observed. Conclusions Of particular clinical significance is that self-esteem can modulate the stress levels of women exposed to IPV, a valuable insight into the development of effective psychosocial interventions to support IPV victims in sub-Saharan Africa

Different Mi-2 Complexes for Various Developmental Functions in Caenorhabditis elegans

Biochemical purifications from mammalian cells and Xenopus oocytes revealed that vertebrate Mi-2 proteins reside in multisubunit NuRD (Nucleosome Remodeling and Deacetylase) complexes. Since all NuRD subunits are highly conserved in the genomes of C. elegans and Drosophila, it was suggested that NuRD complexes also exist in invertebrates. Recently, a novel dMec complex, composed of dMi-2 and dMEP-1 was identified in Drosophila. The genome of C. elegans encodes two highly homologous Mi-2 orthologues, LET-418 and CHD-3. Here we demonstrate that these proteins define at least three different protein complexes, two distinct NuRD complexes and one MEC complex. The two canonical NuRD complexes share the same core subunits HDA-1/HDAC, LIN-53/RbAp and LIN-40/MTA, but differ in their Mi-2 orthologues LET-418 or CHD-3. LET-418 but not CHD-3, interacts with the Krüppel-like protein MEP-1 in a distinct complex, the MEC complex. Based on microarrays analyses, we propose that MEC constitutes an important LET-418 containing regulatory complex during C. elegans embryonic and early larval development. It is required for the repression of germline potential in somatic cells and acts when blastomeres are still dividing and differentiating. The two NuRD complexes may not be important for the early development, but may act later during postembryonic development. Altogether, our data suggest a considerable complexity in the composition, the developmental function and the tissue-specificity of the different C. elegans Mi-2 complexes

The Chromatin Remodeler LET-418/Mi2 is Required Cell Non-Autonomously for the Post-Embryonic Development of Caenorhabditis elegans

Chromatin condition is crucial for the cells to respond to their environment. In C. elegans, post-embryonic development is accompanied by the exit of progenitor cells from quiescence in response to food. The chromatin protein LET-418/Mi2 is required for this transition in development indicating that proper chromatin structure in cells of the freshly hatched larvae is important to respond to food. However, the identity of the tissue or cells where LET-418/Mi2 is required, as well as the developmental signals that it is modulating have not been elucidated. By restoring the activity of LET-418/Mi2 in specific tissues, we demonstrate that its activity in the intestine and the hypodermis is able to promote in a cell non-autonomous manner the exit of blast cells from quiescence and further development. Furthermore, we identify the IIS (insulin/insulin-like growth factor signaling) pathway to be one of the signaling pathways that is conveying LET-418/Mi2 cell non-autonomous effect on development

Methylation of the glucocorticoid receptor gene (NR3C1) in dyads mother-child exposed to intimate partner violence in Cameroon: Association with anxiety symptoms

Background The glucocorticoid receptor (GR), which is encoded by the NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1) gene plays an important role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis activity by providing feedback regulation which allows termination of the stress response. Little is known about epigenetic programming at the level of NGFI-A (nerve growth factor-inducible protein A) putative binding site (CpG) of the NR3C1 exon 1F in dyads mother-child exposed to intimate partner violence (IPV) more specifically in an unstudied region such as the sub-Saharan Africa where levels of violence are very high. Objective Examine NR3C1 exon 1F methylation in response to IPV and possible association with cortisol concentration and mental health. Method We recruited 20 mother–child dyads exposed to IPV and a control group of 20 mother–child dyads not exposed to IPV. We administered self-reported questionnaires to measure mother’s mental health and collected saliva samples for cortisol dosage and bisulfite sequencing of DNA methylation. Results Regarding the mothers, our results showed a significant difference in methylation level at CpG 16–21 sites of the NR3C1 exon 1F promoter region between the groups. In the exposed group as compared to the control group, there was a significant positive association between the level of methylation at CpG 16–21 sites and mother’s mental health in particular anxiety symptoms. However, we did not find any significant correlation between methylation level and cortisol concentration. In children, we did not find any significant results. Conclusion This study highlights a NGFI-A putative binding site (CpG 16–21) that is more methylated in mothers exposed to IPV and which may have the potential to confer vulnerability for psychopathologies

A Network of Chromatin Factors Is Regulating the Transition to Postembryonic Development in Caenorhabditis elegans

Mi2 proteins are evolutionarily conserved, ATP-dependent chromatin remodelers of the CHD family that play key roles in stem cell differentiation and reprogramming. In Caenorhabditis elegans, the let-418 gene encodes one of the two Mi2 homologs, which is part of at least two chromatin complexes, namely the Nucleosome Remodeling and histone Deacetylase (NuRD) complex and the MEC complex, and functions in larval development, vulval morphogenesis, lifespan regulation, and cell fate determination. To explore the mechanisms involved in the action of LET-418/Mi2, we performed a genome-wide RNA interference (RNAi) screen for suppressors of early larval arrest associated with let-418 mutations. We identified 29 suppressor genes, of which 24 encode chromatin regulators, mostly orthologs of proteins present in transcriptional activator complexes. The remaining five genes vary broadly in their predicted functions. All suppressor genes could suppress multiple aspects of the let-418 phenotype, including developmental arrest and ectopic expression of germline genes in the soma. Analysis of available transcriptomic data and quantitative PCR revealed that LET-418 and the suppressors of early larval arrest are regulating common target genes. These suppressors might represent direct competitors of LET-418 complexes for chromatin regulation of crucial genes involved in the transition to postembryonic development

From the Mother to the Child: The Intergenerational Transmission of Experiences of Violence in Mother–Child Dyads Exposed to Intimate Partner Violence in Cameroon

Intimate partner violence (IPV) is a widespread social problem with serious consequences for the health of both women and their children. However, little is known about the combined effect of maternal childhood abuse and current exposure to IPV with respect to the psychopathological symptoms of the mother–child dyad. In a Cameroonian cultural setting, where IPV affects more than half of women, we aimed to better understand how mother’s childhood abuse and current IPV co-occur to lead to psychopathological symptoms in the mother–child dyad. With the help of a non-governmental organization in Cameroon, we recruited 49 mother–child dyads exposed to IPV, along with 25 mother–child dyads who had not been exposed, and who functioned as a control group. All mothers completed a set of questionnaires, including the Revised Conflict Tactics Scale to assess IPV; the Child Trauma Questionnaire to examine their childhood trauma; the Child Behavior Checklist to assess their children’s psychopathological traits; the Hospital Anxiety and Depression Scale; and the Symptom Checklist. We found that physical abuse experienced by mothers during childhood was associated with IPV in adulthood, and specifically sexual abuse, p = .001. In addition, we found that the accumulation of maternal childhood abuse and current IPV was related to anxiety and depression symptoms in mothers, all R2 ≥ .18, all ps ≤ .015, as well as to externalized symptoms in children, all R2 ≥ .27, all ps ≤ .017. Our results suggest the intergenerational transmission of experiences of childhood abuse and current IPV, which calls for the development of interventions and care strategies for the mother–child dyad