http://bartellab.wi.mit.edu/publication_reprints/Ulitsky_Cell_2013.pdf

lincRNAs: genomics, evolution, and mechanisms.

Modification of Enhancer Chromatin: What, How, and Why?

Cellular development, morphology and function are governed by precise patterns of gene expression. These are established by the coordinated action of genomic regulatory elements known as enhancers or cis-regulatory modules. More than 30 years after the initial discovery of enhancers, many of their properties have been elucidated; however, despite major efforts, we only have an incomplete picture of enhancers in animal genomes. In this Review, we discuss how properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies. We also cover recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity. Finally, we discuss recent technological advances and current challenges in the field of regulatory genomics.

Transcriptional enhancers: from properties to genome-wide predictions.

https://bradleybiology.org/papers/pdf/2013/KlattenhoffEtAl2013.pdf

Braveheart, a Long Noncoding RNA Required for Cardiovascular Lineage Commitment

Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases. This paper demonstrates that de novo mutations with large effect have a role in the pathogenesis of at least 10% of cases of congenital heart disease (CHD). Using exome sequence analysis in parent–offspring trios Richard Lifton and colleagues compared the frequency of de novo mutations, identified by exome sequencing, in 362 CHD parent–offspring trios and 264 control trios. Gene ontology analysis demonstrated significant enrichment of de novo protein-altering mutation of genes involved in chromatin modification, notably a marked enrichment of genes involved in the production, removal and reading of methylation of histone H3K4 and H3K27. Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation2,3,4. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer5. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

/pdf/de-novo-mutations-in-histone-modifying-genes-in-congenital-f8evnr2zsk.pdf

De novo mutations in histone-modifying genes in congenital heart disease

Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage

Toxoplasma gondii is a highly successful protozoan parasite that infects all warm-blooded animals and causes severe disease in immunocompromised and immune-naive humans. It has an unusual global population structure: In North America and Europe, isolated strains fall predominantly into four largely clonal lineages, but in South America there is great genetic diversity and the North American clonal lineages are rarely found. Genetic variation between Toxoplasma strains determines differences in virulence, modulation of host-signaling pathways, growth, dissemination, and disease severity in mice and likely in humans. Most studies on Toxoplasma genetic variation have focused on either a few loci in many strains or low-resolution genome analysis of three clonal lineages. We use whole-genome sequencing to identify a large number of SNPs between 10 Toxoplasma strains from Europe and North and South America. These were used to identify haplotype blocks (genomic regions) shared between strains and construct a Toxoplasma haplotype map. Additional SNP analysis of RNA-sequencing data of 26 Toxoplasma strains, representing global diversity, allowed us to construct a comprehensive genealogy for Toxoplasma gondii that incorporates sexual recombination. These data show that most current isolates are recent recombinants and cannot be easily grouped into a limited number of haplogroups. A complex picture emerges in which some genomic regions have not been recently exchanged between any strains, and others recently spread from one strain to many others.

http://www.pnas.org/content/109/33/13458.full.pdf

Fugen Li

Papers

Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage

Admixture and recombination among Toxoplasma gondii lineages explain global genome diversity