Gastrulation is the fundamental process during the embryogenesis of all multicellular animals through which the basic body plan is first laid down. It is pivotal in generating cellular diversity coordinated with spatial patterning. Gastrulation in humans occurs in the third week following fertilization. Our understanding of this process in humans is extremely limited, and based almost entirely on experimental models. Here, we characterize in a spatially resolved manner the single cell transcriptional profile of an entire gastrulating human embryo approximately 16 to 19 days after fertilization. We used these data to provide the first unequivocal demonstration that human embryonic stem cells represent the early post implantation epiblast. We identified both primordial germ cells and red blood cells, which had never been characterized so early during human development. Comparison with mouse gastrula transcriptomes revealed many commonalities between the human and mouse but also several key differences, particularly in FGF signaling, that we validated experimentally. This unique dataset offers a unique glimpse into a central but generally inaccessible stage of our development, provides new context for interpreting experiments in other model systems and represents a valuable resource for guiding directed differentiation of human cells in vitro.
The TGFβ pathway plays an essential role in embryonic development, organ homeostasis, tissue repair, and disease1,2. This diversity of tasks is achieved through the intracellular effector SMAD2/3, whose canonical function is to control activity of target genes by interacting with transcriptional regulators3. Nevertheless, a complete description of the factors interacting with SMAD2/3 in any given cell type is still lacking. Here we address this limitation by describing the interactome of SMAD2/3 in human pluripotent stem cells (hPSCs). This analysis reveals that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, we identify a functional interaction with the METTL3-METTL14-WTAP complex, which deposits N6-methyladenosine (m6A)4. We uncover that SMAD2/3 promotes binding of the m6A methyltransferase complex onto a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor NANOG, thereby poising them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Collectively, these findings reveal the mechanism by which extracellular signalling can induce rapid cellular responses through regulations of the epitranscriptome. These novel aspects of TGFβ signalling could have far-reaching implications in many other cell types and in diseases such as cancer5.
Gastrulation is the fundamental process during the embryogenesis of all multicellular animals through which the basic body plan is first laid down. It is pivotal in generating cellular diversity coordinated with spatial patterning. Gastrulation in humans occurs in the third week following fertilization. Our understanding of this process in humans is extremely limited, and based almost entirely on experimental models. Here, we characterize in a spatially resolved manner the single cell transcriptional profile of an entire gastrulating human embryo approximately 16 to 19 days after fertilization. We used these data to provide the first unequivocal demonstration that human embryonic stem cells represent the early post implantation epiblast. We identified both primordial germ cells and red blood cells, which had never been characterized so early during human development. Comparison with mouse gastrula transcriptomes revealed many commonalities between the human and mouse but also several key differences, particularly in FGF signaling, that we validated experimentally. This unique dataset offers a unique glimpse into a central but generally inaccessible stage of our development, provides new context for interpreting experiments in other model systems and represents a valuable resource for guiding directed differentiation of human cells in vitro.
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