Fetal hemoglobin (HbF, α2γ2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2β2) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects ...expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.
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•BCL11A recognizes TGACCA motif in vitro and in vivo through zinc-finger domain•BCL11A acts at distal TGACCA in human γ-globin promoters to silence expression•TGACCA motif is mutated in individuals with HPFH syndrome•Editing the distal TGACCA prevents BCL11A binding and reactivates γ-globin expression
The developmental transition between fetal and adult hemoglobin is controlled by a repressor that acts directly at the γ-globin gene promoter, suggesting a simplified control mechanism that could be manipulated in treatment of γ-hemoglobin disorders.
A major challenge in biology is to understand how complex gene expression patterns are encoded in the genome. While transcriptional enhancers have been studied extensively, few transcriptional ...silencers have been identified, and they remain poorly understood. Here, we used a novel strategy to screen hundreds of sequences for tissue-specific silencer activity in whole Drosophila embryos. Almost all of the transcriptional silencers that we identified were also active enhancers in other cellular contexts. These elements are bound by more transcription factors than non-silencers. A subset of these silencers forms long-range contacts with promoters. Deletion of a silencer caused derepression of its target gene. Our results challenge the common practice of treating enhancers and silencers as separate classes of regulatory elements and suggest the possibility that thousands or more bifunctional CRMs remain to be discovered in Drosophila and 104–105 in humans.
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•Silencers are bifunctional and can act as enhancers in other cellular contexts•A subset of silencers forms long-range contacts to promoters•Deletion of a silencer by genome editing caused derepression of its target gene•Results suggest that thousands of bifunctional elements in flies remain to be discovered
Gisselbrecht et al. performed a screen in developing Drosophila embryos for genomic sequences that can act as transcriptional silencers. They report that nearly all silencers are enhancers in other tissues or at other developmental stages. Their silencers fall into two classes, one of which forms physical chromosomal contacts with promoters.
The evolution of transcriptional regulatory networks entails the expansion and diversification of transcription factor (TF) families. The forkhead family of TFs, defined by a highly conserved winged ...helix DNA-binding domain (DBD), has diverged into dozens of subfamilies in animals, fungi, and related protists. We have used a combination of maximum-likelihood phylogenetic inference and independent, comprehensive functional assays of DNA-binding capacity to explore the evolution of DNA-binding specificity within the forkhead family. We present converging evidence that similar alternative sequence preferences have arisen repeatedly and independently in the course of forkhead evolution. The vast majority of DNA-binding specificity changes we observed are not explained by alterations in the known DNA-contacting amino acid residues conferring specificity for canonical forkhead binding sites. Intriguingly, we have found forkhead DBDs that retain the ability to bind very specifically to two completely distinct DNA sequence motifs. We propose an alternate specificity-determining mechanism whereby conformational rearrangements of the DBD broaden the spectrum of sequence motifs that a TF can recognize. DNA-binding bispecificity suggests a previously undescribed source of modularity and flexibility in gene regulation and may play an important role in the evolution of transcriptional regulatory networks.
Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely ...unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.
The insula is structurally abnormal in schizophrenia, demonstrating reductions in volume, cortical thickness, and altered gyrification during prodromal, early and chronic stages of the illness. ...Despite compelling structural alterations, less is known about its functional connectivity, limited by studies considering the insula as a whole or only within the context of resting-state networks. There is evidence, however, from healthy subjects that the insula is comprised of sub-regions with distinct functional profiles, with dorsal anterior insula (dAI) involved in cognitive processing, ventral anterior insula (vAI) involved in affective processing, and posterior insula (PI) involved in somatosensory processing. The current study builds on this prior work and characterizes insula resting-state functional connectivity sub-region profiles in a large cohort of schizophrenia (N = 191) and healthy (N = 196) participants and hypothesizes specific associations between insula sub-region connectivity abnormalities and clinical characteristics related to their functional profiles. Functional dysconnectivity of the insula in schizophrenia is broadly characterized by reduced connectivity within insula sub-networks and greater connectivity with regions not normally connected with that sub-region, reflected in significantly greater similarity of dAI and PI connectivity profiles and significantly lower similarity of dAI and vAI connectivity profiles (p < .05). In schizophrenia, reduced connectivity of dAI correlates with cognitive function (r = 0.18, p = .014), whereas stronger connectivity between vAI and superior temporal sulcus correlates with negative symptoms (r = 0.27, p < .001). These findings reveal altered insula connectivity in all three sub-regions and converge with recent evidence of reduced differentiation of insula connectivity in schizophrenia, implicating functional dysconnectivity of the insula in cognitive and clinical symptoms.
Effective risk communication is an integral part of responding to terrorism, but until recently, there has been very little pre‐event communication in a European context to provide advice to the ...public on how to protect themselves during an attack. Following terrorist attacks involving mass shootings in Paris, France, in November 2015, the U.K. National Police Chiefs’ Council released a Stay Safe film and leaflet that advises the public to “run,” “hide,” and “tell” in the event of a firearms or weapons attack. However, other countries, including Denmark, do not provide preparedness information of this kind, in large part because of concern about scaring the public. In this survey experiment, 3,003 U.K. and Danish participants were randomly assigned to one of three conditions: no information, a leaflet intervention, and a film intervention to examine the impact of “Run, Hide, Tell” advice on perceptions about terrorism, the security services, and intended responses to a hypothetical terrorist firearms attack. Results demonstrate important benefits of pre‐event communication in relation to enhancing trust, encouraging protective health behaviors, and discouraging potentially dangerous actions. However, these findings also suggest that future communications should address perceived response costs and target specific problem behaviors. Cross‐national similarities in response suggest this advice is suitable for adaptation in other countries.
•Thalamus connectivity with sensory cortical regions decrease during development.•Thalamus connectivity with heteromodal cortical regions increase during development.•Increased thalamus connectivity ...with visual regions in females.•Increased thalamus connectivity with orbitofrontal regions in males.•Decreased thalamus connectivity with frontal regions in psychosis spectrum youth.
The thalamus is composed of multiple nuclei densely connected with the cortex in an organized manner, forming parallel thalamocortical networks critical to sensory, motor, and cognitive functioning. Thalamocortical circuit dysfunction has been implicated in multiple neurodevelopmental disorders, including schizophrenia, which also often exhibit sex differences in prevalence, clinical characteristics, and neuropathology. However, very little is known about developmental and sex effects on thalamocortical networks in youth. The present study characterized the effects of age, sex and psychosis symptomatology in anatomically constrained thalamocortical networks in a large community sample of youth (n = 1100, aged 8–21) from the Philadelphia Neurodevelopmental Cohort (PNC). Cortical functional connectivity of seven anatomically defined thalamic nuclear groups were examined: anterior, mediodorsal, ventral lateral, ventral posterolateral, pulvinar, medial and lateral geniculate nuclear groups. Age and sex effects were characterized using complementary thalamic region-of-interest (ROI) to cortical ROI and voxel-wise analyses. Effects of clinical symptomatology were analyzed by separating youth into three groups based on their clinical symptoms; typically developing youth (n = 298), psychosis spectrum youth (n = 320), and youth with other psychopathologies (n = 482). As an exploratory analysis, association with PRIME scores were used as a dimensional measure of psychopathology. Age effects were broadly characterized by decreasing connectivity with sensory/motor cortical areas, and increasing connectivity with heteromodal prefrontal and parietal cortical areas. This pattern was most pronounced for thalamic motor and sensory nuclei. Females showed greater connectivity between multiple thalamic nuclear groups and the visual cortex compared to males, while males showed greater connectivity with the inferior frontal and orbitofrontal cortices. Youth with psychosis spectrum symptoms showed a subtle decrease in thalamic connectivity with the premotor and prefrontal cortices. Across all youth, greater PRIME scores were associated with lower connectivity between the prefrontal cortex and mediodorsal thalamus. By characterizing typical development in anatomically constrained thalamocortical networks, this study provides an anchor for conceptualizing disruptions to the integrity of these networks observed in neurodevelopmental disorders.
Across networks, connectivity within the frontoparietal network (FPN) and cingulo-opercular network (CON) exhibits reductions earliest during healthy aging, contributing to cognitive impairment. ...Individuals with psychotic disorders demonstrate evidence of accelerated aging across multiple biological systems. By leveraging a large sample of patients with psychosis from early to chronic illness stages, this study sought to determine whether the CON and FPN exhibit evidence of accelerated aging in psychotic disorders, confirm associations between network efficiency and cognition, and determine whether reduced network efficiency is observed in early-stage psychosis.
Resting-state functional magnetic resonance imaging and cognitive data were obtained on 240 patients with psychotic disorder and 178 healthy control participants (HCs). Global efficiency, a measure of functional integration, was calculated for the CON, FPN, subcortical network, and visual network. Associations with age and cognition were assessed and compared between groups.
Consistent with accelerated aging, significant group by age interactions reflected significantly stronger relationships between efficiency and age in patients with psychosis than in HCs for both the CON (psychosis: r = −.37; HC: r = −.16) and FPN (psychosis: r = −.31; HC: r = −.05). Accelerated aging was not observed in either the subcortical or visual network, suggesting specificity for cognitive networks that decline earliest in healthy aging. Replicating prior findings, efficiency of both the CON and FPN correlated with cognitive function across all participants (rs > .11, ps < .031). Furthermore, patients with chronic psychosis (p = .004), but not patients with early psychosis (p = .553), exhibited significantly lower FPN efficiency compared with HCs.
Functional integration of higher-order cognitive networks is intact in early psychosis but exhibits evidence of accelerated aging, suggesting the potential for intervention targeting cognition within the early psychosis period.
A majority of children admitted to a single hospital in late 2021–early 2022 with acute hepatitis of unknown cause tested positive for adenovirus. This report describes the children’s illnesses and ...outcomes.
Researchers have studied the online sexual grooming of minors extensively since the early 2000s. However, the grooming process is neither new nor restricted to digital media. While grooming and child ...sexual abuse existed long before the Internet, the advent of the Internet has resulted in more ways in which offenders can interact with candidate victims including offline-only, online-only, and a mix of offline and online.
In this study, we conducted a scoping review of grooming strategies both pre- and post-Internet. Our goal was to enumerate strategies analyzed in both time periods, provide similarities and differences, and discuss how changing datasets and technology have impacted the grooming process in both online and offline environments.
We performed a scoping review of peer-reviewed journal articles from 1970 to 2020 within PubMed, Medline, PsychInfo, and ERIC. This resulted in 19,679 unique articles. Titles and abstracts were screened resulting in 266 articles which were then read in full, resulting in 93 papers which qualified based on inclusion criteria.
Grooming strategies identified pre-Internet included: enticements, coercion, isolation, substance abuse, gradual sexualization, and secrecy. In comparison, the strategies identified post-Internet were: enticements, risk assessment, trust, sexualization, fantasy, secrecy, isolation, meeting, media progression, deception, coercion, substance use as a tool, authority, and repetition.
While grooming strategies overlapped pre and post-Internet, the timing and scope of concepts differed. Additionally, grooming offline began to incorporate technology post-Internet which functioned to increase accessibility and isolation of the victim in a similar manner to online grooming.
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