Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

A comparative encyclopedia of DNA elements in the mouse genome

Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to the formation of a totipotent embryo. During the development of the pre-implantation embryo, precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality, but the underlying molecular mechanisms remain elusive. For the past few years, unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development, taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies. The aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals, including DNA methylation, histone modifications, chromatin accessibility and 3D chromatin organization.

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Insights into epigenetic patterns in mammalian early embryos

Summary Upon fertilization, terminally differentiated gametes are transformed to a totipotent zygote, which gives rise to an embryo. How parental epigenetic memories are inherited and reprogrammed to accommodate parental-to-zygotic transition remains a fundamental question in developmental biology, epigenetics, and stem cell biology. With the rapid advancement of ultra-sensitive or single-cell epigenome analysis methods, unusual principles of epigenetic reprogramming begin to be unveiled. Emerging data reveal that in many species, the parental epigenome undergoes dramatic reprogramming followed by subsequent re-establishment of the embryo epigenome, leading to epigenetic "rebooting." Here, we discuss recent progress in understanding epigenetic reprogramming and their functions during mammalian early development. We also highlight the conserved and species-specific principles underlying diverse regulation of the epigenome in early embryos during evolution.

Rebooting the Epigenomes during Mammalian Early Embryogenesis

Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer

N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, plays important roles in tuning the chromatin state and transcription, but the intrinsic mechanism remains unclear. Here, we report that YTHDC1 plays indispensable roles in the self-renewal and differentiation potency of mouse embryonic stem cells (ESCs), which highly depends on the m6A-binding ability. Ythdc1 is required for sufficient rRNA synthesis and repression of the 2-cell (2C) transcriptional program in ESCs, which recapitulates the transcriptome regulation by the LINE1 scaffold. Detailed analyses revealed that YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates the formation of the LINE1-NCL partnership and the chromatin recruitment of KAP1. Moreover, the establishment of H3K9me3 on 2C-related retrotransposons is interrupted in Ythdc1-depleted ESCs and inner cell mass (ICM) cells, which consequently increases the transcriptional activities. Our study reveals a role of m6A in regulating the RNA scaffold, providing a new model for the RNA-chromatin cross-talk.

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Nuclear m 6 A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

The oocyte cytoplasm can reprogram the somatic cell nucleus into a totipotent state, but with low efficiency. The spatiotemporal chromatin organization of somatic cell nuclear transfer (SCNT) embryos remains elusive. Here, we examine higher order chromatin structures of mouse SCNT embryos using a low-input Hi-C method. We find that donor cell chromatin transforms to the metaphase state rapidly after SCNT along with the dissolution of typical 3D chromatin structure. Intriguingly, the genome undergoes a mitotic metaphase-like to meiosis metaphase II-like transition following activation. Subsequently, weak chromatin compartments and topologically associating domains (TADs) emerge following metaphase exit. TADs are further removed until the 2-cell stage before being progressively reestablished. Obvious defects including stronger TAD boundaries, aberrant super-enhancer and promoter interactions are found in SCNT embryos. These defects are partially caused by inherited H3K9me3, and can be rescued by Kdm4d overexpression. These observations provide insight into chromatin architecture reorganization during SCNT embryo development. The organisation of chromatin in somatic cell nuclear transfer (SCNT) embryos remains poorly understood. Here, the authors examine higher order chromatin structures of mouse SCNT embryos and provide insights into chromatin architecture reorganisation during SCNT embryo development.

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Chromatin architecture reorganization in murine somatic cell nuclear transfer embryos

N6-methyladenosine (m6A) on chromosome-associated regulatory RNAs (carRNAs), including repeat RNAs, play important roles in tuning the chromatin state and transcription1. Among diverse RNA-chromatin interacting modes, the nuclear RNA scaffold is considered important for trans-interactions2,3 but has not yet been connected with m6A yet. Here, we found that Ythdc1 played indispensable roles in the embryonic stem cell (ESC) self-renewal and differentiation potency, and these roles highly depended on its m6A-binding ability. Ythdc1 deficiency in ESCs resulted in decreased rRNA synthesis and the activation of 2-cell (2C) embryo-specific transcriptional program, and these observations recapitulated the transcriptome defects induced by dysfunction of the long interspersed nuclear element-1 (LINE1)-scaffold, which were unrelated to the direct targeting of Ythdc1. A detailed analysis revealed that Ythdc1 recognized m6A on LINE1 and was physically involved in the formation of the LINE1-Nucleolin partnership and the chromatin recruitment of Kap1. In summary, our study reveals a new link between m6A and the RNA scaffold and thus provides a new regulatory model for the crosstalk between RNA and the chromatin epigenome.

Lingyue Yang

Papers

Nuclear m 6 A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

Chromatin architecture reorganization in murine somatic cell nuclear transfer embryos

Nuclear m6A reader Ythdc1 regulates the scaffold function of LINE1 in mouse ESCs