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Background CREB and CREM are closely related factors that regulate transcription in response to various stress, metabolic and developmental signals. The CREMτ activator isoform is selectively expressed in haploid spermatids and plays an essential role in murine spermiogenesis. Results We have used chromatin immunoprecipitation coupled to sequencing (ChIP-seq) to map CREM and CREB target loci in round spermatids from adult mouse testis and spermatogonia derived GC1-spg cells respectively. We identify more than 9000 genomic loci most of which are cell-specifically occupied. Despite the fact that round spermatids correspond to a highly specialised differentiated state, our results show that they have a remarkably accessible chromatin environment as CREM occupies more than 6700 target loci corresponding not only to the promoters of genes selectively expressed in spermiogenesis, but also of genes involved in functions specific to other cell types. The expression of only a small subset of these target genes are affected in the round spermatids of CREM knockout animals. We also identify a set of intergenic binding loci some of which are associated with H3K4 trimethylation and elongating RNA polymerase II suggesting the existence of novel CREB and CREM regulated transcripts. Conclusions We demonstrate that CREM and CREB occupy a large number of promoters in highly cell specific manner. This is the first study of CREM target promoters directly in a physiologically relevant tissue in vivo and represents the most comprehensive experimental analysis of CREB/CREM regulatory potential to date.

Background Anorexia nervosa (AN) is a serious multifactorial eating disorder characterized by insufficient nutritional intake to maintain a minimum normal weight for one's age and height, a fear of gaining weight and a distorted body image. It affects mainly adolescents, but a decreased age at diagnosis has been reported, leading to the definition of a rare form of AN called early-onset or prepubertal anorexia nervosa (EOAN; ORPHA 525738), with reported epidemiological and clinical specificity. Current knowledge and specific treatments for this particular condition remain scarce. We aim to summarize the literature review and synthesize actual knowledge on EOAN for preliminary guidelines to harmonize the diagnosis, treatment and follow-up. Methods A scoping literature review was performed from 2010-2021 using PubMed, Web of Science, PsycInfo and Cochrane via the following search terms: (anorexia nervosa) AND (early-onset OR premenarchal OR prepubertal OR childhood). International guidelines were screened for additional hits. Data extraction was limited to findings relevant to the key topic questions: epidemiology and clinical specificities section, diagnosis and initial evaluation section, treatment section, and follow-up and prognosis section. Results A total of 1257 titles were retrieved via the initial search strategy. Finally, 42 records were included in the present article (30 articles and 11 international guidelines and 1 literature review). We identified 15 articles relevant for the epidemiology and clinical specificities section, 11 for the diagnosis and initial evaluation section, 3 for the treatment section, and 1 for the follow-up and prognosis section. Despite the growing literature on the epidemiological and clinical features of EOAN, knowledge of specific treatments and prognoses remains scarce in the absence of extensive standardized data collection and few age-specific clinical research protocols. Current international guidelines generally extrapolate strategies proposed for adolescents and young adults to children with a low level of evidence. Conclusions Continuing research efforts in this specific younger population is needed to validate child-specific care strategies, enabling the establishment of age-appropriate recommendations with a higher level of evidence targeting specific determinants and clinical specificities of EOAN. Plain English summary Anorexia nervosa (AN) is a serious multifactorial eating disorder characterized by insufficient nutritional intake to maintain a minimum normal weight for one’s age and height, a fear of gaining weight and a distorted body image. It affects mainly adolescents, but a decreased age at diagnosis has been reported, leading to the definition of a rare form of AN called early-onset or prepubertal anorexia nervosa (EOAN; ORPHA 525738), with reported epidemiological and clinical specificity. Current knowledge and specific treatments for this particular condition remain scarce. The aim of this study is to summarize the literature review and synthesize actual knowledge on EOAN for preliminary guidelines to harmonize the diagnosis, treatment and follow-up of AN in this specific younger population to promote early diagnosis and appropriate multidisciplinary management to improve the prognosis for children with EOAN.

Background: Microbial-associated molecular patterns activate several MAP kinases, which are major regulators of the innate immune response in Arabidopsis thaliana that induce large-scale changes in gene expression. Here, we determine whether microbial-associated molecular pattern-triggered gene expression involves modifications at the chromatin level. Results: Histone acetylation and deacetylation are major regulators of microbial-associated molecular pattern-triggered gene expression and implicate the histone deacetylase HD2B in the reprogramming of defence gene expression and innate immunity. The MAP kinase MPK3 directly interacts with and phosphorylates HD2B, thereby regulating the intra-nuclear compartmentalization and function of the histone deacetylase. Conclusions: By studying a number of gene loci that undergo microbial-associated molecular pattern-dependent activation or repression, our data reveal a mechanistic model for how protein kinase signaling directly impacts chromatin reprogramming in plant defense.

Background: Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored. Results: In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome-free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms. Conclusions: These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions.

Epigenetic alterations are documented in several models of Huntington’s disease (HD). However, it remains unclear whether similar alterations also occur in HD patients. Using the striatum of HD R6/1 mice and genome-wide approaches, we found that down-regulated genes display a particular epigenetic signature and this signature is altered in HD mouse striatum. We showed that H3K27ac signal is selectively decreased at super-enhancers, a category of enhancers regulating cell-type specific genes. Our results suggest that the mechanism linking epigenetic and transcriptional defects in HD striatum involves altered expression of non-coding RNA expressed from super-enhancers (seRNAs). To assess whether the mechanism is conserved in HD patients, we generated H3K27ac ChIP-seq data from the striatum of HD patients and control individuals. Our results indicate that striatal super-enhancer signature is also altered in HD patients. Together, our data support a model where altered epigenetic regulation of super-enhancers would be responsible for gene down-regulation in HD brain tissues. We suggest that targeting enhancer activity may be of therapeutic interest.

Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. In the mouse ovary, oestrogen receptors and FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying their protective effect is unknown. Here, we show that TRIM28 is required to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of Trim28, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type, different from gonadal embryonic progenitors. TRIM28 is recruited on chromatin in the proximity of FOXL2 to maintain the ovarian pathway and to repress testicular-specific genes. The role of TRIM28 in ovarian maintenance depends on its E3-SUMO ligase activity that regulates the sex-specific SUMOylation profile of ovarian-specific genes. Our study identifies TRIM28 as a key factor in protecting the adult ovary from the testicular pathway. Competing Interest Statement The authors have declared no competing interest. Footnotes * -the text of the manuscript -the expression of SOX9/SO8 and FOXL2 -The SUMOylation

Abstract Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells. Competing Interest Statement The authors have declared no competing interest.

The pathogenesis of Lassa fever has not yet been fully deciphered, particularly as concerns the mechanisms determining whether acute infection is controlled or leads to catastrophic illness and death. Using a cynomolgus monkey model of Lassa virus (LASV) infection reproducing the different outcomes of the disease, we performed histological and transcriptomic studies to investigate the dynamics of LASV infection and the immune mechanisms associated with survival or death. Lymphoid organs are an early major reservoir for replicating virus during Lassa fever, with LASV entering through the cortical sinus of draining lymph nodes regardless of disease outcome. However, subsequent viral tropism varies considerably with disease severity, with viral dissemination limited almost entirely to lymphoid organs and immune cells during nonfatal Lassa fever. By contrast, the systemic dissemination of LASV to all organs and diverse cell types, leading to infiltrations with macrophages and neutrophils and an excessive inflammatory response, is associated with a fatal outcome. These results provide new insight into early viral dynamics and the host response to LASV infection according to disease outcome.

Lassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine. Lassa virus vaccination is impeded by the limited capacity of vaccine candidates to induce rapid protection. In this study, the authors found that a single shot of a measles-based Lassa vaccine protected nonhuman primates 16 or 8 days after vaccination.

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.Baillet et al. use the cynomolgus monkey model to model Lassa virus and associated Lassa fever (LF). They provide a full characterisation of LF pathogenesis with the aim of assisting the development of early diagnostic tools.