The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Chromatin state annotation using combinations of chromatin modification patterns has emerged as a powerful approach for discovering regulatory regions and their cell type specific activity patterns, and for interpreting disease-association studies1-5. However, the computational challenge of learning chromatin state models from large numbers of chromatin modification datasets in multiple cell types still requires extensive bioinformatics expertise making it inaccessible to the wider scientific community. To address this challenge, we have developed ChromHMM, an automated computational system for learning chromatin states, characterizing their biological functions and correlations with large-scale functional datasets, and visualizing the resulting genome-wide maps of chromatin state annotations.

ChromHMM: automating chromatin-state discovery and characterization

Noncoding DNA regions have central roles in human biology, evolution, and disease. ChromHMM helps to annotate the noncoding genome using epigenomic information across one or multiple cell types. It combines multiple genome-wide epigenomic maps, and uses combinatorial and spatial mark patterns to infer a complete annotation for each cell type. ChromHMM learns chromatin-state signatures using a multivariate hidden Markov model (HMM) that explicitly models the combinatorial presence or absence of each mark. ChromHMM uses these signatures to generate a genome-wide annotation for each cell type by calculating the most probable state for each genomic segment. ChromHMM provides an automated enrichment analysis of the resulting annotations to facilitate the functional interpretations of each chromatin state. ChromHMM is distinguished by its modeling emphasis on combinations of marks, its tight integration with downstream functional enrichment analyses, its speed, and its ease of use. Chromatin states are learned, annotations are produced, and enrichments are computed within 1 d.

Chromatin-state discovery and genome annotation with ChromHMM

Environmental epigenetics and epigenetic inheritance in domestic farm animals.

Sperm miRNAs were reported to regulate spermatogenesis and early embryonic development in some mammals including bovine. The dairy cattle breeding industry now tends to collect semen from younger bulls under high selection pressure at a time when semen quality may be suboptimal compared to adult bulls. Whether the patterns of spermatic miRNAs are affected by paternal age and/or impact early embryogenesis is not clear. Hence, we generated small non-coding RNA libraries of sperm collected from same bulls at 10, 12, and 16 months of age, using 16 months as control for differential expression and functional analysis. We firstly excluded all miRNAs present in measurable quantity in oocytes according to the literature. Of the remaining miRNAs, ten sperm-borne miRNAs were significantly differentially expressed in younger bulls (four in the 10 vs 16 months contrast and six in the 12 vs 16 months contrast). Targets of miRNAs were identified and compared to the transcriptomic database of two-cell embryos, to genes related to two-cell competence, and to the transcriptomic database of blastocysts. Ingenuity pathway analysis of the targets of these miRNAs suggested potential influence on the developmental competence of two-cell embryos and on metabolism and protein synthesis in blastocysts. The results showed that miRNA patterns in sperm are affected by the age of the bull and may mediate the effects of paternal age on early embryonic development.

/pdf/sperm-mirnas-potential-mediators-of-bull-age-and-early-zocmtopt9n.pdf

Sperm miRNAs- potential mediators of bull age and early embryo development.

The age of the bull influences the transcriptome and epigenome of blastocysts produced by IVF.

The bovine represents an important agriculture species and dairy breeds have experienced intense genetic selection over the last decades. The selection of breeders focused initially on milk production, but now includes feed efficiency, health, and fertility, although these traits show lower heritability. The non-genetic paternal and maternal effects on the next generation represent a new research topic that is part of epigenetics. The evidence for embryo programming from both parents is increasing. Both oocytes and spermatozoa carry methylation marks, histones modifications, small RNAs, and chromatin state variations. These epigenetic modifications may remain active in the early zygote and influence the embryonic period and beyond. In this paper, we review parental non-genetic effects retained in gametes on early embryo development of dairy cows, with emphasis on parental age (around puberty), the metabolism of the mother at the time of conception and in vitro culture (IVC) conditions. In our recent findings, transcriptomic signatures and DNA methylation patterns of blastocysts and gametes originating from various parental and IVC conditions revealed surprisingly similar results. Embryos from all these experiments displayed a metabolic signature that could be described as an "economy" mode where protein synthesis is reduced, mitochondria are considered less functional. In the absence of any significant phenotype, these results indicated a possible similar adaptation of the embryo to younger parental age, post-partum metabolic status and IVC conditions mediated by epigenetic factors.

/pdf/parental-effects-on-epigenetic-programming-in-gametes-and-4gl66nnvza.pdf

Chongyang Wu

Papers

Sperm miRNAs- potential mediators of bull age and early embryo development.

The age of the bull influences the transcriptome and epigenome of blastocysts produced by IVF.

Parental Effects on Epigenetic Programming in Gametes and Embryos of Dairy Cows