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While footprinting analysis of ATAC-seq data can theoretically enable investigation of transcription factor (TF) binding, the lack of a computational tool able to conduct different levels of footprinting analysis has so-far hindered the widespread application of this method. Here we present TOBIAS, a comprehensive, accurate, and fast footprinting framework enabling genome-wide investigation of TF binding dynamics for hundreds of TFs simultaneously. We validate TOBIAS using paired ATAC-seq and ChIP-seq data, and find that TOBIAS outperforms existing methods for bias correction and footprinting. As a proof-of-concept, we illustrate how TOBIAS can unveil complex TF dynamics during zygotic genome activation in both humans and mice, and propose how zygotic Dux activates cascades of TFs, binds to repeat elements and induces expression of novel genetic elements. Footprinting analysis allows genome-wide investigation of transcription factor (TF) binding on chromatin. Here the authors developed a framework termed TOBIAS aimed at identifying footprints of chromatin-associated proteins from ATAC-seq accessibility profiles and apply it to zygotic development datasets.

Induced pluripotent stem cells (iPSCs) can self-renew indefinitely in culture and differentiate into all specialized cell types including gametes. iPSCs do not exist naturally and are instead generated (“induced” or “reprogrammed”) in culture from somatic cells through ectopic co-expression of defined pluripotency factors. Since they can be generated from any healthy person or patient, iPSCs are considered as a valuable resource for regenerative medicine to replace diseased or damaged tissues. In addition, reprogramming technology has provided a powerful tool to study mechanisms of cell fate decisions and to model human diseases, thereby substantially potentiating the possibility to (i) discover new drugs in screening formats and (ii) treat life-threatening diseases through cell therapy-based strategies. However, various legal and ethical barriers arise when aiming to exploit the full potential of iPSCs to minimize abuse or unauthorized utilization. In this review, we discuss bioethical, legal, and societal concerns associated with research and therapy using iPSCs. Furthermore, we present key questions and suggestions for stem cell scientists, legal authorities, and social activists investigating and working in this field.

Ectopic expression of Oct4, Sox2, Klf4 and c-Myc can reprogram somatic cells into induced pluripotent stem cells (iPSCs). Attempts to identify genes or chemicals that can functionally replace each of these four reprogramming factors have revealed that exogenous Oct4 is not necessary for reprogramming under certain conditions or in the presence of alternative factors that can regulate endogenous Oct4 expression. For example, polycistronic expression of Sox2, Klf4 and c-Myc can elicit reprogramming by activating endogenous Oct4 expression indirectly. Experiments in which the reprogramming competence of all other Oct family members tested and also in different species have led to the decisive conclusion that Oct proteins display different reprogramming competences and species-dependent reprogramming activity despite their profound sequence conservation. We discuss the roles of the structural components of Oct proteins in reprogramming and how donor cell epigenomes endow Oct proteins with different reprogramming competences. Stem cells: Mechanisms for reprogramming cells Cells can be reprogrammed into induced pluripotent stem cells (iPSCs), embryonic-like stem cells that can turn into any cell type and have extensive potential medical uses, without adding the transcription factor OCT4. Although other nearly identical OCT family members had been tried, only OCT4 could induce reprogramming and was previously thought to be indispensable. However, it now appears that the reprogramming can be induced by multiple pathways, as detailed in a review by Hans Schöler, Max Planck Institute for Biomolecular Medicine, Münster, and Johnny Kim, Max Planck Institute for Heart and Lung Research, Bad Nauheim, in Germany. They report that any factors that trigger cells to activate endogeous OCT4 can produce iPSCs without exogeously admistration of OCT4. The mechanisms for producing iPSCs can differ between species. These results illuminate the complex mechanisms of reprogramming.

Satellite cells are muscle stem cells required for muscle regeneration upon damage. Of note, satellite cells are bipotent and have the capacity to differentiate not only into skeletal myocytes, but also into brown adipocytes. Epigenetic mechanisms regulating fate decision and differentiation of satellite cells during muscle regeneration are not yet fully understood. Here, we show that elevated levels of lysine-specific demethylase 1 (Kdm1a, also known as Lsd1) have a beneficial effect on muscle regeneration and recovery after injury, since Lsd1 directly regulates key myogenic transcription factor genes. Importantly, selective Lsd1 ablation or inhibition in Pax7-positive satellite cells, not only delays muscle regeneration, but changes cell fate towards brown adipocytes. Lsd1 prevents brown adipocyte differentiation of satellite cells by repressing expression of the novel pro-adipogenic transcription factor Glis1. Together, downregulation of Glis1 and upregulation of the muscle-specific transcription program ensure physiological muscle regeneration. Satellite cells can differentiate both into myocytes and brown adipocytes. Here, the authors show that the histone demethylase Lsd1 prevents adipogenic differentiation of satellite cells by repressing expression of Glis1, and that its ablation changes satellite cell fate towards brown adipocytes and delays muscle regeneration in mice.

In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates. The transcription factor double homeobox protein (DUX) induces a totipotency-specific regulatory program, including the upregulation of DUXBL. DUXBL subsequently accesses DUX-bound regions and interacts with TRIM24 and TRIM33, thus contributing to totipotency exit.

Skeletal muscle stem cells (MuSC), also called satellite cells, are indispensable for maintenance and regeneration of adult skeletal muscles. Yet, a comprehensive picture of the regulatory events controlling the fate of MuSC is missing. Here, we determine the proteome of MuSC to design a loss-of-function screen, and identify 120 genes important for MuSC function including the arginine methyltransferase Prmt5. MuSC-specific inactivation of Prmt5 in adult mice prevents expansion of MuSC, abolishes long-term MuSC maintenance and abrogates skeletal muscle regeneration. Interestingly, Prmt5 is dispensable for proliferation and differentiation of Pax7 + myogenic progenitor cells during mouse embryonic development, indicating significant differences between embryonic and adult myogenesis. Mechanistic studies reveal that Prmt5 controls proliferation of adult MuSC by direct epigenetic silencing of the cell cycle inhibitor p21 . We reason that Prmt5 generates a poised state that keeps MuSC in a standby mode, thus allowing rapid MuSC amplification under disease conditions. Skeletal muscle satellite cells are important for muscle regeneration, but their regulatory mechanisms are largely unknown. Here the authors identify arginine methyltransferase Prmt5 as a key regulator of satellite cell maintenance and function in adult mice, and show that Prmt5 acts mainly but not exclusively on the cell cycle inhibitor p21.

Solution-focused brief therapy (SFBT) is an empirically-supported psychotherapeutic intervention in treating mental health issues in the general population. When being delivered to adolescents and young adults (AYAs) diagnosed with cancer, specific techniques and skills of SFBT need to be tailored to meet the unique bio-psycho-social challenges of the AYA cancer population. Using a patient-centered approach, our team interviewed 14 AYAs with cancer who received SFBT for cancer (SFBT-C) to inform the tailoring and refinement of the existing SFBT intervention specifically for the AYA cancer population. Themes emerged within three broad categories that informed the tailoring and refinement of SFBT for AYAs with cancer, i.e., general experiences, strengths, and weaknesses of SFBT-C. AYAs with cancer found SFBT-C overall positively different from other approaches. Strengths include SFBT-C’s collaborative nature, using positive emotion as an important change mechanism, and a good balance between being relevant to cancer and not focusing too much on their cancer. Areas of improvement include assignment flexibility and different strategies to address resistance. The findings of this paper significantly inform the delivery of SFBT-C to AYAs with cancer using patient-centered feedback and input.

The growing mental health needs of students within schools have resulted in teachers increasing their involvement in the delivery of school-based, psychosocial interventions. Current research reports mixed findings concerning the effectiveness of psychosocial interventions delivered by teachers for mental health outcomes. This article presents a systematic review and meta-analysis that examined the effectiveness of school-based psychosocial interventions delivered by teachers on internalizing and externalizing outcomes and the moderating factors that influence treatment effects on these outcomes. Nine electronic databases, major journals, and gray literature (e.g., websites, conference abstract) were searched and field experts were contacted to locate additional studies. Twenty-four studies that met the study inclusion criteria were coded into internalizing or externalizing outcomes and further analyzed using robust variance estimation in meta-regression. Both publication and risk of bias of studies were further assessed. The results showed statistically significant reductions in students’ internalizing outcomes ( d  = .133, 95% CI [.002, .263]) and no statistical significant effect for externalizing outcomes ( d  = .15, 95% CI [−.037, .066]). Moderator analysis with meta-regression revealed that gender (%male, b  = −.017, p  < .05), race (% Caucasian, b  = .002, p  < .05), and the tier of intervention ( b  = .299, p  = .06) affected intervention effectiveness. This study builds on existing literature that shows that teacher-delivered Tier 1 interventions are effective interventions but also adds to this literature by showing that interventions are more effective with internalizing outcomes than on the externalizing outcomes. Moderator analysis also revealed treatments were more effective with female students for internalizing outcomes and more effective with Caucasian students for externalizing outcomes.

Adolescents and young adults (AYAs) diagnosed with cancer are an age-defined population, with studies reporting up to 45% of the population experiencing psychological distress. Although it is essential to screen and monitor for psychological distress throughout AYAs’ cancer journeys, many cancer centers fail to effectively implement distress screening protocols largely due to busy clinical workflow and survey fatigue. Recent advances in mobile technology and speech science have enabled flexible and engaging methods to monitor psychological distress. However, patient-centered research focusing on these methods’ feasibility and acceptability remains lacking. Therefore, in this project, we aim to evaluate the feasibility and acceptability of an artificial intelligence (AI)-enabled and speech-based mobile application to monitor psychological distress among AYAs diagnosed with cancer. We use a single-arm prospective cohort design with a stratified sampling strategy. We aim to recruit 60 AYAs diagnosed with cancer and to monitor their psychological distress using an AI-enabled speech-based distress monitoring tool over a 6 month period. The primary feasibility endpoint of this study is defined by the number of participants completing four out of six monthly distress assessments, and the acceptability endpoint is defined both quantitatively using the acceptability of intervention measure and qualitatively using semi-structured interviews.

B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7 , a transcription factor, and Phip , a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology. Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.