Sox17 and ß-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mukherjee, S., Chaturvedi, P., Rankin, S. A., Fish, M. B., Wlizla, M., Paraiso, K. D., MacDonald, M., Chen, X., Weirauch, M. T., Blitz, I. L., Cho, K. W. Y., & Zorn, A. M. Sox17 and ß-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network. Elife, 9, (2020): e58029, doi:10.7554/eLife.58029.Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD073179) Ken WY Cho Aaron M Zorn National Institute of Diabetes and Digestive and Kidney Diseases (P30DK078392) Aaron M Zorn Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD093363) Aaron M Zor

A systematic review of reviews of correctional mental health services using the STAIR Framework

Background: Rising demand for correctional mental health services (CMHS) in recent decades has been a global phenomenon. Despite increasing research, there are major gaps in understanding the best models for CMHS and how to measure their effectiveness, particularly studies that consider the overall care pathways and effectiveness of service responses. The STAIR (Screening, Triage, Assessment, Intervention, and Re-integration) model is an evidence-based framework that defines and measures CMHS as a clinical pathway with a series of measurable, and linked functions. Method: We conducted a systematic review of the reviews of CMHS elements employing PRISMA guidelines, organized according to STAIR pillars. We assessed the quality of included studies using the AMSTAR-2 criteria. Narrative reviews were read and results synthesized. Results: We included 26 review articles of which 12 were systematic, metaanalyses, and 14 narrative reviews. Two systematic reviews and seven narrative reviews addressed screening and triage with strong evidence to support specific screening and triage systems. There was no evidence for standardised assessment approaches. Eight systematic reviews and seven narrative reviews addressed interventions providing some evidence to support specific psychosocial interventions. Three systematic reviews and six narrative reviews addressed reintegration themes finding relatively weak evidence to support reintegration methods, with interventions often being jurisdictionally specific and lacking generalizability. Conclusions: The STAIR framework is a useful way to organize the extant literature. More research is needed on interventions, assessment systems, care pathway evaluations, and reintegration models

Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts

Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts

Uncovering the mesendoderm gene regulatory network through multi-omic data integration.

Mesendodermal specification is one of the earliest events in embryogenesis, where cells first acquire distinct identities. Cell differentiation is a highly regulated process that involves the function of numerous transcription factors (TFs) and signaling molecules, which can be described with gene regulatory networks (GRNs). Cell differentiation GRNs are difficult to build because existing mechanistic methods are low throughput, and high-throughput methods tend to be non-mechanistic. Additionally, integrating highly dimensional data composed of more than two data types is challenging. Here, we use linked self-organizing maps to combine chromatin immunoprecipitation sequencing (ChIP-seq)/ATAC-seq with temporal, spatial, and perturbation RNA sequencing (RNA-seq) data from Xenopus tropicalis mesendoderm development to build a high-resolution genome scale mechanistic GRN. We recover both known and previously unsuspected TF-DNA/TF-TF interactions validated through reporter assays. Our analysis provides insights into transcriptional regulation of early cell fate decisions and provides a general approach to building GRNs using highly dimensional multi-omic datasets