Software for Computing and Annotating Genomic Ranges

Despite recent progress in genome topology knowledge, the role of repeats, which make up the majority of mammalian genomes, remains elusive. Satellite repeats are highly abundant sequences that cluster around centromeres, attract pericentromeric heterochromatin, and aggregate into nuclear chromocenters. These nuclear landmark structures are assumed to form a repressive compartment in the nucleus to which genes are recruited for silencing. We have designed a strategy for genome-wide identification of pericentromere-associated domains (PADs) in different mouse cell types. The ∼1000 PADs and non-PADs have similar chromatin states in embryonic stem cells, but during lineage commitment, chromocenters progressively associate with constitutively inactive genomic regions at the nuclear periphery. This suggests that PADs are not actively recruited to chromocenters, but that chromocenters are themselves attracted to inactive chromatin compartments. However, we also found that experimentally induced proximity of an active locus to chromocenters was sufficient to cause gene repression. Collectively, our data suggest that rather than driving nuclear organization, pericentromeric satellite repeats mostly co-segregate with inactive genomic regions into nuclear compartments where they can contribute to stable maintenance of the repressed status of proximal chromosomal regions.[Supplemental material is available for this article.]One of the major challenges in genome biology is to understand how the genome is organized and what factors control the spatiotemporal expression patterns of genes in different cell types. It is well established that higher-order organization of chromatin within the three-dimensional space of the nucleus is an important contributor to regulation of gene expression. In particular, long-range physical interactions of genomic elements in the nuclear space enable functional communication between genes and their regulatory DNA elements that can be hundreds of kilobases apart on the linear

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“…Manipulation with and computation of statistics on genomic intervals and domains was done using the GenomicRanges package (Lawrence et al 2013). …”

Section: Resultsmentioning

confidence: 99%

Characterization and dynamics of pericentromere-associated domains in mice

et al. 2015

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“…Sequence reads were counted according to overlaps on exon models obtained from the ensGene database from the University of California, Santa Cruz (UCSC), genome browser (54). The database was downloaded in January 2011 using R software 3.2.2 (55) and processed using the Bioconductor (56, 57) packages rtracklayer (58), Rsamtools (59), GenomicRanges (60), and GenomicFeatures (60). A set of genes that was not annotated in the Ensembl database but that was annotated in the refGene database from the UCSC genome browser was analyzed in conjunction with the Ensembl annotation.…”

Section: Methodsmentioning

confidence: 99%

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Biase

Rabel

Guillomot

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A major unresolved issue in the cloning of mammals by somatic cell nuclear transfer (SCNT) is the mechanism by which the process fails after embryos are transferred to the uterus of recipients before or during the implantation window. We investigated this problem by using RNA sequencing (RNA-seq) to compare the transcriptomes in cattle conceptuses produced by SCNT and artificial insemination (AI) at day (d) 18 (preimplantation) and d 34 (postimplantation) of gestation. In addition, endometrium was profiled to identify the communication pathways that might be affected by the presence of a cloned conceptus, ultimately leading to mortality before or during the implantation window. At d 18, the effects on the transcriptome associated with SCNT were massive, involving more than 5,000 differentially expressed genes (DEGs). Among them are 121 genes that have embryonic lethal phenotypes in mice, cause defects in trophoblast and placental development, and/or affect conceptus survival in mice. In endometria at d 18, <0.4% of expressed genes were affected by the presence of a cloned conceptus, whereas at d 34, ∼36% and <0.7% of genes were differentially expressed in intercaruncular and caruncular tissues, respectively. Functional analysis of DEGs in placental and endometrial tissues suggests a major disruption of signaling between the cloned conceptus and the endometrium, particularly the intercaruncular tissue. Our results support a "bottleneck" model for cloned conceptus survival during the periimplantation period determined by gene expression levels in extraembryonic tissues and the endometrial response to altered signaling from clones. somatic cell nuclear transfer | conceptus | placentation | conceptus-maternal communication I n cattle, as in other mammals, exquisitely orchestrated physiological changes of the conceptus and uterus are necessary for a successful pregnancy. Synchronization of the complex events at the time of implantation relies on the timed release of molecular signals from the conceptus and the endometrium. Embryo-derived IFN-τ (IFNT) is the major signal of pregnancy in cattle, preventing luteolysis and regulating the expression of genes that are responsible for promoting local changes in the endometrium to accommodate the conceptus (1-3). In females, progesterone is the major driver of endometrial changes that prepare the uterus for conceptus implantation (4, 5). In addition to IFNT and progesterone, signaling between the bovine conceptus and the endometrium is bidirectional, and involves several pathways that work concomitantly (6) for the successful establishment of pregnancy.Independent studies have shown that the majority of embryonic losses in cattle occur during the period that spans embryo cleavage until the attachment of the blastocyst to the endometrium (7). The reasons for these losses remain unclear and likely result from several factors, including embryonic lethal genes (8, 9), environmental stressors (7), and endometrial condition (10). Cloning of cattle by somatic cell nuclear transfer ...

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“…Reproducibility Plots-Reads per kilobase per million mapped reads (RPKM) for each differentially expressed gene was calculated by the R Bioconductor package GenomicRanges (37). The heat map was generated according to the count table with scaling across the samples for each gene.…”

Section: Methodsmentioning

confidence: 99%

Kruppel-like Factor-9 (KLF9) Inhibits Glioblastoma Stemness through Global Transcription Repression and Integrin α6 Inhibition

Ying

Tilghman

Wei

et al. 2014

Journal of Biological Chemistry

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Background: Cancer cell stemness determines tumor propagation and malignancy by poorly defined mechanisms. Results: The KLF9 transcription factor regulates cell fate and oncogenic pathways by repressing gene transcription in glioblastoma stem cells. Conclusion: KLF9 inhibits glioblastoma cell stemness and tumor growth by directly repressing genes, including ITGA6. Significance: KLF9 and its transcriptional network are potential targets for regulating cancer stem cells and glial malignancies.

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Software for Computing and Annotating Genomic Ranges

Cited by 3,578 publications

References 10 publications

Characterization and dynamics of pericentromere-associated domains in mice

Characterization and dynamics of pericentromere-associated domains in mice

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Kruppel-like Factor-9 (KLF9) Inhibits Glioblastoma Stemness through Global Transcription Repression and Integrin α6 Inhibition

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