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The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we have shown that deletion of Chd7 from cerebellar granule cell progenitors (GCps) results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice. Genome-wide expression profiling revealed downregulated expression of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps. Recessive RELN mutations have been associated with severe cerebellar hypoplasia in humans. We found molecular and genetic evidence that reductions in Reln expression contribute to GCp proliferative defects and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we showed that CHD7 is necessary for maintaining an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln, and provides direct in vivo evidence that a mammalian CHD protein can control brain development by modulating chromatin accessibility in neuronal progenitors.

Neuronal specification, expansion and differentiation are tightly regulated by the concerted actions of transcription and chromatin modifying factors that are recruited to regulatory elements in the genome. Tissue-specific distal regulatory elements are typically located tens to hundreds of kilobases from the gene they regulate. Thus, to identify the distal enhancers that directly regulate a gene, information on the localisation of enhancers relative to the gene promoter in the nucleus is crucial. Cerebellar granule cell progenitors (GCps) are important transit amplifying neuronal progenitors, giving rise to the most abundant neuronal cell type in the brain. Many of the key factors that regulate fundamental developmental processes in GCps have been identified. For instance, the proneural transcription factor Atoh1 is essential for GCp specification, proliferation and differentiation and the ATP-dependent chromatin remodeller CHD7 is necessary for normal GCp proliferation and differentiation. However, both these factors are recruited to distal regulatory elements and the direct regulatory relationships between these factors, the enhancers they are recruited to, and the genes they regulate in GCps remain uncharacterised. To identify active, long-range gene regulatory interactions in GCps, we used promoter capture Hi-C (pcHi-C), and integrated pcHi-C data with ATAC-seq and ChIP-seq data. We present a rich dataset consisting of 46,428 interactions between 22,797 putative distal regulatory regions and 12,905 protein coding gene promoters in primary mouse GCps. Using VISTA-designated hindbrain enhancers as an example, we identify the genes most likely regulated directly by these enhancers and update their annotation accordingly. Motif enrichment analyses identified a significant enrichment of proneural transcription factor motifs in CHD7-regulated enhancers. Further analyses revealed co-localisation of Atoh1 and CHD7 at gene enhancers, suggesting a novel regulatory relationship between Atoh1 and CHD7 in controlling the expression of key genes in the GCp lineage. We used our data to identify >1,500 Atoh-regulated enhancers, contacting the promoters of 577 genes in GCps, and 197 enhancers of 22 genes that appear to be co-regulated by Atoh1 and CHD7. Co-immunoprecipitation experiments showed that Atoh1 and CHD7 proteins interact with each other. These findings support the emerging picture of CHD7 as an important gene regulatory co-factor for lineage-specific transcription factors. The pcHi-C data is presented as a useful resource to the community for investigating the function of long-range enhancers in the cerebellar GCp lineage.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We include luciferase assays as functional validation for some of the putative enhancers identified by our work (Suppl Fig. 3). We also include a comparative analysis between our data and the Reddy et al. Hi-C dataset (Suppl. Fig. 1) and a comparison between embryonic VISTA hindbrain enhancers and our P7 GCp ATAC-seq data in Fig. 1.Funder Information DeclaredMedical Research Council, https://ror.org/03x94j517, MR/K022377/1, MR/Y008170/1Medical Research Council, https://ror.org/03x94j517, G1000902Wellcome Trust, 224619/Z/21/Z

Despite a link between adverse childhood experiences (ACEs) and anxiety, the role of anxiety in the pathway to chronic pain is unclear. Potentially, inflammatory biomarkers such as C-reactive protein (CRP) are involved. Objectives were to (1) examine relationships between reported ACEs, anxiety, and chronic pain, and (2) assess associations between ACEs, anxiety, and CRP levels and between CRP and chronic pain. Data from 24,172 adults who participated in the UK Biobank were used to conduct Poisson regressions to assess relationships between ACEs, anxiety, and chronic pain. For participants with CRP data who met the inclusion criteria (n = 2007), similar models were run between ACEs, anxiety, and CRP, and CRP and chronic pain. For objective 1, three statistically significant interactions were found to predict pain: frequency of physical abuse x reported muscular symptoms during anxiety ( p  = 0.01); frequency in which they felt hated x having discussed anxiety with a professional ( p  = 0.03), and reported frequency of sexual abuse x difficulties relaxing during anxiety attacks ( p  = 0.03). For objective 2, frequency of sexual abuse and informing a professional about anxiety significantly interacted to predict elevated CRP. For correlations, the largest was between CRP and the number of times pain was reported over the years ( p  = 0.01). Finally, ACEs (physical abuse, sexual abuse, and whether taken to a doctor) significantly interacted with CRP to predict pain. This study suggests mechanisms of the impact of ACEs on chronic pain may include inflammation and anxiety, which warrants further study.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven ( CAMK2D , PRKD1 , PRKD3 , MAPK3 , TNFSF12 , APOC3 and NAE1 ) proteins as potential targets for interventions to be used in primary prevention of heart failure. Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.

Purpose To examine children’s experiences of chemotherapy-induced cognitive impairment––colloquially “chemobrain”––and the impact on children’s social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors’ lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child’s own voice and/or parent proxy report through an exploration of the qualitative research literature. Methods A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0–18 years) during and/or following chemotherapy treatment and explored children’s experiences of chemobrain. Results Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children’s experiences primarily related to changes in their academic and social functioning. Conclusion This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field.

Because of their role in mediating life‐history trade‐offs, hormones are expected to be strongly associated with components of fitness; however, few studies have examined how natural selection acts on hormonal variation in the wild. In a songbird, the dark‐eyed junco (Junco hyemalis), field experiments have shown that exogenous testosterone alters individuals’ resolution of the survival‐reproduction trade‐off, enhancing reproduction at the expense of survival. Here we used standardized injections of gonadotropin‐releasing hormone (GnRH) to assay variation in the testosterone production of males. Using measurements of annual survival and reproduction, we found evidence of strong natural selection acting on GnRH‐induced increases in testosterone. Opposite to what would be predicted from the survival‐reproduction trade‐off, patterns of selection via survival and reproduction were remarkably similar. Males with GnRH‐induced testosterone production levels that were slightly above the population mean were more likely to survive and also produced more offspring, leading to strong stabilizing selection. Partitioning reproduction into separate components revealed positive directional selection via within‐pair siring success and stabilizing selection via extrapair mating success. Our data represent the most complete demonstration of natural selection on hormones via multiple fitness components, and they complement previous experiments to illuminate testosterone’s role in the evolution of life‐history trade‐offs.

Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.

Heart failure (HF) has limited therapeutic options. In this study, we differentiated the pathophysiological underpinnings of the HF subtypes—HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)—and uncovered subtype-specific therapeutic strategies. We investigated the causal roles of the human proteome and transcriptome using Mendelian randomization on more than 420,000 participants from the Million Veteran Program (27,799 HFrEF and 27,579 HFpEF cases). We created therapeutic target profiles covering efficacy, safety, novelty, druggability and mechanism of action. We replicated findings on more than 175,000 participants of diverse ancestries. We identified 70 HFrEF and 10 HFpEF targets, of which 58 were not previously reported; notably, the HFrEF and HFpEF targets are non-overlapping, suggesting the need for subtype-specific therapies. We classified 14 previously unclassified HF loci as HFrEF. We substantiated the role of ubiquitin–proteasome system, small ubiquitin-related modifier pathway, inflammation and mitochondrial metabolism in HFrEF. Among druggable genes, IL6R , ADM and EDNRA emerged as potential HFrEF targets, and LPA emerged as a potential target for both subtypes. Combining human proteome and transcriptome analyses and Mendelian randomization on a large genetic dataset of HFpEF and HFrEF cases, Rasooly et al. identified 58 potential therapeutic targets specific for either HEpEF or HFrEF and created their therapeutic target profiles.