Histone modifications are fundamental epigenetic regulators that control many crucial cellular processes. However, whether these marks can be passed on from mammalian gametes to the next generation is a long-standing question that remains unanswered. Here, by developing a highly sensitive approach, STAR ChIP-seq, we provide a panoramic view of the landscape of H3K4me3, a histone hallmark for transcription initiation, from developing gametes to post-implantation embryos. We find that upon fertilization, extensive reprogramming occurs on the paternal genome, as H3K4me3 peaks are depleted in zygotes but are readily observed after major zygotic genome activation at the late two-cell stage. On the maternal genome, we unexpectedly find a non-canonical form of H3K4me3 (ncH3K4me3) in full-grown and mature oocytes, which exists as broad peaks at promoters and a large number of distal loci. Such broad H3K4me3 peaks are in contrast to the typical sharp H3K4me3 peaks restricted to CpG-rich regions of promoters. Notably, ncH3K4me3 in oocytes overlaps almost exclusively with partially methylated DNA domains. It is then inherited in pre-implantation embryos, before being erased in the late two-cell embryos, when canonical H3K4me3 starts to be established. The removal of ncH3K4me3 requires zygotic transcription but is independent of DNA replication-mediated passive dilution. Finally, downregulation of H3K4me3 in full-grown oocytes by overexpression of the H3K4me3 demethylase KDM5B is associated with defects in genome silencing. Taken together, these data unveil inheritance and highly dynamic reprogramming of the epigenome in early mammalian development.

TGFbeta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFbeta responses are generally mediated through transcriptional functions of Smads. A key step in TGFbeta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFbeta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFbeta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Calpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFbeta-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFbeta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling.

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Highlights d RNA-BisSeq revealed a dynamic RNA m 5 C landscape during zebrafish embryogenesis d Ybx1 preferentially recognizes m 5 C-modified mRNAs d Ybx1 deficiency leads to early gastrulation defects in zebrafish embryos d Ybx1 and Pabpc1a coordinately regulate m 5 C-modified maternal mRNA stability

Cerebrovascular dysfunction is strongly associated with neonatal intracranial hemorrhage (ICH) and stroke in adults. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable cerebral circulation in the central nervous system by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-β (TGF-β) signaling, specifically in the cerebral ECs, results in perinatal ICH and blood-brain barrier breakdown. Furthermore, the mutant vessels exhibit defective mural cell coverage. Smad4 stabilizes cerebrovascular EC-pericyte interactions by regulating the transcription of N-cadherin through associating with the Notch intracellular complex at the RBP-J binding site of the N-cadherin promoter. These findings uncover a distinct role of endothelial Smad4 in maintaining cerebrovascular integrity and suggest important implications for genetic or functional deficiencies in TGF-β/Smad signaling in the pathogenesis of cerebrovascular dysfunction.

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Nodal proteins, members of the transforming growth factor-beta (TGFbeta) superfamily, have been identified as key endogenous mesoderm inducers in vertebrates. Precise control of Nodal signaling is essential for normal development of embryos. Here, we report that zebrafish dapper2 (dpr2) is expressed in mesoderm precursors during early embryogenesis and is positively regulated by Nodal signals. In vivo functional studies in zebrafish suggest that Dpr2 suppresses mesoderm induction activities of Nodal signaling. Dpr2 is localized in late endosomes, binds to the TGFbeta receptors ALK5 and ALK4, and accelerates lysosomal degradation of these receptors.

A growing body of evidence indicates that second-generation energy crops can play an important role in the development of renewable energy and the mitigation of climate change. However, dedicated energy crops have yet to be domesticated in order to fully realize their productive potential under unfavorable soil and climatic conditions. To explore the possibility of domesticating Miscanthus crops in northern China where marginal and degraded land is abundant, we conducted common garden experiments at multiple locations to evaluate variation and adaptation of three Miscanthus species that are likely to serve as the wild progenitors of the energy crops. A total of 93 populations of Miscanthus sinensis, Miscanthus sacchariflorus, and Miscanthus lutarioriparius were collected across their natural distributional ranges in China and grown in three locations that represent temperate grassland with cold winter, the semiarid Loess Plateau, and relatively warm and wet central China. Evaluated with growth traits such as plant height, tiller number, tiller diameter, and flowering time, the Miscanthus species showed high levels of genetic variation within and between species. There were significant site  population interactions for almost all traits of M. sacchariflorus and M. sinensis, but not M. lutarioriparius. The northern populations of M. sacchariflorus had the highest establishment rates at the most northern site owing to their strong cold tolerance. An endemic species in central China, M. lutarioriparius, produced not only the highest biomass of the three species but also higher biomass at the Loess Plateau than the southern site near its native habitats. These results demonstrated that the wild species harbored a high level of genetic variation underlying traits important for crop establishment and production at sites that are colder and drier than their native habitats. The natural variation and adaptive plasticity found in the Miscanthus species indicated that they could provide valuable resources for the development of second-generation energy crops.