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The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 is a transcription factor that acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CPs remains unknown. Here, by combining ChIP–seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the dynamic remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We identified Zic2 and Zic3 as essential cofactors that act with Mesp1 to regulate its transcription-factor activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development. Lin, Swedlund et al. report that Mesp1 governs the remodelling of the chromatin and enhancer landscape during differentiation of early mesodermal cells into distinct populations of cardiovascular progenitors.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein–associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.

Traditionally, the mouse has been the favoured vertebrate model for biomedical research, due to its experimental and genetic tractability. However, non-rodent embryological studies highlight that many aspects of early mouse development, such as its egg-cylinder gastrulation and method of implantation, diverge from other mammals, thus complicating inferences about human development. Like the human embryo, rabbits develop as a flat-bilaminar disc. Here we constructed a morphological and molecular atlas of rabbit development. We report transcriptional and chromatin accessibility profiles for over 180,000 single cells and high-resolution histology sections from embryos spanning gastrulation, implantation, amniogenesis and early organogenesis. Using a neighbourhood comparison pipeline, we compare the transcriptional landscape of rabbit and mouse at the scale of the entire organism. We characterize the gene regulatory programmes underlying trophoblast differentiation and identify signalling interactions involving the yolk sac mesothelium during haematopoiesis. We demonstrate how the combination of both rabbit and mouse atlases can be leveraged to extract new biological insights from sparse macaque and human data. The datasets and computational pipelines reported here set a framework for a broader cross-species approach to decipher early mammalian development, and are readily adaptable to deploy single-cell comparative genomics more broadly across biomedical research. Ton, Keitley et al. provide a morphological and molecular atlas of rabbit development. Comparative studies reveal that combining rabbit and mouse atlases can serve as a model for dissecting early primate development.

The rabbit is an important model species for developmental and translational research. Here, we used histological imaging and single-cell transcriptomics to characterize gastrulation and early organogenesis in the rabbit. We identified substantial transcriptional differences between the rabbit and mouse, highlighting the power of cross-species comparative genomics to elucidate early human development.

Biomedical research relies heavily on the use of model organisms to gain insight into human health and development. Traditionally, the mouse has been the favored vertebrate model, due to its experimental and genetic tractability. Non-rodent embryological studies however highlight that many aspects of early mouse development, including the egg-cylinder topology of the embryo and its method of implantation, diverge from other mammals, thus complicating inferences about human development. In this study, we constructed a morphological and molecular atlas of rabbit development, which like the human embryo, develops as a flat-bilaminar disc. We report transcriptional and chromatin accessibility profiles of almost 180,000 single cells and high-resolution histology sections from embryos spanning gastrulation, implantation, amniogenesis, and early organogenesis. Using a novel computational pipeline, we compare the transcriptional landscape of rabbit and mouse at the scale of the entire organism, revealing that extra-embryonic tissues, as well as gut and PGC cell types, are highly divergent between species. Focusing on these extra-embryonic tissues, which are highly accessible in the rabbit, we characterize the gene regulatory programs underlying trophoblast differentiation and identify novel signaling interactions involving the yolk sac mesothelium during hematopoiesis. Finally, we demonstrate how the combination of both rabbit and mouse atlases can be leveraged to extract new biological insights from sparse macaque and human data. The datasets and analysis pipelines reported here set a framework for a broader cross-species approach to decipher early mammalian development, and are readily adaptable to deploy single cell comparative genomics more broadly across biomedical research. Competing Interest Statement J.A.-R. and T.K.A are employed by Novo Nordisk. B.G. has received research funding from Novo Nordisk. Footnotes * https://marionilab.github.io/RabbitGastrulation2022/ * https://marionilab.github.io/ExtendedMouseAtlas/

Perturbation studies using gene knockouts have become a key tool for understanding the roles of regulatory genes in development and disease. Here we systematically characterise the knockout effects of the key developmental regulators T and Mixl1 in chimeric mouse embryos during gastrulation and organogenesis. We present a comprehensive and effective suite of statistical tools for systematic characterisation of effects at the level of differential abundance of cell types, lineage development, and gene dysregulation. Applying our computational approach to a novel chimera data set with Mixl1 knockout reveals a disruption in Epicardium development in the absence of Mixl1, characterized by lack of upregulation of the key transcription factor Tbx18 and the Wnt regulator Sfrp5, and by dysregulation of the recently identified juxta-cardiac field. Finally, we demonstrate the wider utility of our framework by applying it to published acute myeloid leukemia (AML) patient data, and show how different responses to therapy are reflected in changes in gene expression along the myeloid trajectory between healthy and AML patients.Competing Interest StatementJ.C.M. has been an employee of Genentech since September 2022. The remaining authors declare no competing interests.Footnotes* We included new results on heart development and an additional Figure (Fig. 4).

STAT3 signalling has been studied extensively in the context of self-renewal and differentiation of mouse embryonic stem cells. Zygotic STAT3 is required for normal postimplantation development. On an outbred genetic background, Stat3 null embryos consistently lagged behind their littermates, beginning with significant reduction of epiblast cells at implantation. Remarkably, mutants closely resemble non-affected embryos from the previous day at all postimplantation stages examined. We pinpoint this phenotype to loss of the serine-phosphorylated form of STAT3 which predominates in postimplantation embryonic tissues. Bulk RNA-sequencing analysis of isolated mouse epiblasts confirmed Stat3 null embryos exhibited developmental delay transcriptionally. Single cell RNA sequencing of mid gestation chimaeras containing STAT3 null embryonic stem cells revealed exclusion of mutant cells exclusively from the erythroid lineage. Although Stat3 null embryonic stem cells can differentiate into erythroid and hematopoietic lineages in vitro, they are out-competed when mixed with wild type cells. Combined with the reduced size of STAT3 null epiblasts after implantation, our results implicate a role for STAT3 in cell proliferation affecting temporal control of embryonic progression and rapid differentiation. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

During mouse gastrulation, extraembryonic mesoderm (ExEM) contributes to the extraembryonic yolk sac (YS) and allantois, both of which are essential for successful gestation. Although the genetic networks coordinating intra-embryonic mesodermal subtype specification are well-studied, the mechanisms driving ExEM diversification are poorly understood. Here, we reveal that embryoid body in vitro differentiation generates two distinct lineages of mesodermal cells matching YS and allantois respectively. Combining in vitro models with in vivo chimeric embryo analysis, we discover that Eomesodermin (Eomes) regulates the formation of a subset of YS-fated ExEM but is dispensable for allantois formation. Furthermore, simultaneous disruption of Eomes and T impedes the specification of any YS or allantois mesoderm, indicating compensatory roles for T during allantois formation when Eomes is disrupted. Our study highlights previously unrecognized functional and mechanistic diversity in ExEM diversification and endothelial development and introduces a tractable EB model to dissect the signaling pathways and transcriptional networks driving the formation of key extraembryonic tissues.

Early organogenesis represents a key step in animal development, where pluripotent cells divide and diversify to initiate formation of all major organs. Here, we used scRNA-Seq to profile over 300,000 single cell transcriptomes sampled in 6 hour intervals from mouse embryos between E8.5 and E9.5. Combining this dataset with our previous E6.5 to E8.5 atlas resulted in a densely sampled time course of over 400,000 cells from early gastrulation to organogenesis. Computational lineage reconstruction at full organismal scale identified complex waves of blood and endothelial development, including a new molecular programme for somite-derived endothelium. To assess developmental fates across the primitive streak, we dissected the E7.5 primitive streak into four adjacent regions, performed scRNA- Seq and predicted cell fates computationally. We next defined early developmental state/fate relationships experimentally by a combination of orthotopic grafting, microscopic analysis of graft contribution as well as scRNA-Seq to transcriptionally determine cell fates of the grafted primitive streak regions after 24h of in vitro embryo culture. Experimentally determined fate outcomes were in good agreement with the fates predicted computationally, thus demonstrating how classical grafting experiments can be revisited to establish high-resolution cell state/fate relationships. Such interdisciplinary approaches will benefit future studies in both developmental biology as well as guide the in vitro production of cells for organ regeneration and repair.

Cet article est consacré à l’identité religieuse et aux pratiques rituelles contemporaines des Cham Ahiér du centre-sud du Vietnam (provinces de Bình Thuận et Ninh Thuận). La compréhension contemporaine de l’identité Cham découle d’un certain nombre d’ouvrages novateurs publiés par des érudits coloniaux français. Cependant, la réflexion passée sur le rôle central des religions « indianisées » (hindouisme et bouddhisme) dans la formation des croyances et pratiques religieuses des Chams a été récemment remise en cause par des publications consacrées à la croissance des pratiques islamiques au cours du deuxième millénaire de notre ère. Bien que la communauté Cham contemporaine soit divisée en groupes qui ont hérité de ces différentes traditions religieuses, les Chams du centre-sud maintiennent un niveau relativement élevé de cohérence ethnique et culturelle grâce à une référence au concept de dualisme cosmologique Ahiér-Awal qui est fortement promu par les intellectuels Cham eux-mêmes. Ce concept dualiste permet de transcender les conflits religieux entre les communautés des Chams dits « hindouistes » et ceux dits « musulmans ». Cet article décrit les complexités actuelles de l’identité religieuse des Chams Ahiér à travers une analyse de leurs pratiques rituelles. Il aborde la communauté des Chams Ahiér et ses pratiques religieuses dans le contexte plus large du milieu religieux afin d’expliquer comment différentes sources de traditions religieuses ont été appropriées et entrelacées, tout en pointant les tensions existant dans ce processus. This article is devoted to the religious identity and ritual practices of the contemporary Cham Ahier of south-central Vietnam (Bình Thuận and Ninh Thuận provinces). Contemporary understanding of Cham identity was derived from a number of groundbreaking works published by French colonial scholars. However, past thinking about the central role of “Indianized” religions (Hinduism and Buddhism) in the formation of Cham religious beliefs and practices was challenged by more recent publications focused on the growth of Islamic practices in the second millennium CE. Although the contemporary Cham community is divided into different groups that inherited these historic religious differences, the southcentral Cham maintain a relatively high level of ethnic and cultural coherence through a reference to the concept of Ahier-Awal cosmological dualism, one which is heavily promoted by Cham intellectuals. This dualist concept helps transcend the religious conflicts between the Cham Ahier (“Cham Hindu”) and Cham Awal (“Cham Muslim”). This article describes the complexities of Cham Ahier religious identity through an analysis of their ritual practices. It approaches the Cham Ahier community and its religious practices within the broader context of the religious milieu, explaining how different sources of religious traditions were appropriated and intertwined, while, at the same time, acknowledging that there were also tensions involved in this process. Bài viết này nghiên cứu vấn đề bản sắc tôn giáo và thực hành nghĩ lễ của người Chăm Ahiér hiện đang sống ở khu vực Nam Trung Bộ Việt Nam (tỉnh Bình Thuận và Ninh Thuận). Những hiểu biết hiện có về bản sắc tôn giáo Chăm phần lớn đều dựa trên những công trình mang tính đột phá được xuất bản bởi các học giả người Pháp. Tuy nhiên, những nghiên cứu trước đây đề cập đến vai trò trung tâm của Ấn Độ giáo và Phật giáo trong việc hình thành tín ngưỡng và thực hành tôn giáo của người Chăm đã bị thử thách bởi các nghiên cứu gần đây nhấn mạnh đến sự phát triển của việc thực hành Hồi giáo trong thiên niên kỷ thứ hai Công nguyên. Mặc dù cộng đồng người Chăm đã chia thành nhiều nhóm do thừa hưởng những tôn giáo khác nhau qua các dòng chảy lịch sử, nhưng người Chăm ở khu vực Nam Trung Bộ hiện nay vẫn duy trì một mức độ gắn kết văn hoá và dân tộc tương đối cao bởi họ cùng thực hành tôn giáo thông qua thuyết “cấu trúc lưỡng hợp” Ahiér-Awal, vốn được trí thức Chăm đề cao. Khái niệm “lưỡng hợp” này đã giúp Chăm Ahiér (“Chăm ảnh hưởng Ấn Độ giáo”) và Chăm Awal (“Chăm ảnh hưởng Hồi giáo”) vượt qua những khác biệt về tôn giáo. Bài viết này mô tả sự phức tạp của vấn đề bản sắc tôn giáo của người Chăm Ahiér qua việc phân tích một số nghi lễ của họ. Thông qua việc tiếp cận thực hành tôn giáo của người Chăm Ahiér trong bối cảnh môi trường tôn giáo rộng lớn, bài viết giải thích sự hiện diện, hoà nhập và đan xen của các nguồn tôn giáo, tín ngưỡng khác nhau chính đã tạo nên tôn giáo Chăm Ahiér hôm nay, đồng thời thừa nhận rằng xuyên suốt quá trình đó, cũng có lúc đã xảy ra những xung đột và căng thẳng.