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Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features.

ABSTRACT: To initiate X-Chromosome inactivation (XCI), the long noncoding RNA Xist mediates chromosome-wide gene silencing of one X Chromosome in female mammals to equalize gene dosage between the sexes. The efficiency of gene silencing is highly variable across genes, with some genes even escaping XCI in somatic cells. A gene's susceptibility to Xist-mediated silencing appears to be determined by a complex interplay of epigenetic and genomic features; however, the underlying rules remain poorly understood. We have quantified chromosome-wide gene silencing kinetics at the level of the nascent transcriptome using allele-specific Precision nuclear Run-On sequencing (PRO-seq). We have developed a Random Forest machine-learning model that can predict the measured silencing dynamics based on a large set of epigenetic and genomic features and tested its predictive power experimentally. The genomic distance to the Xist locus, followed by gene density and distance to LINE elements, are the prime determinants of the speed of gene silencing. Moreover, we find two distinct gene classes associated with different silencing pathways: a class that requires Xist-repeat A for silencing, which is known to activate the SPEN pathway, and a second class in which genes are premarked by Polycomb complexes and tend to rely on the B repeat in Xist for silencing, known to recruit Polycomb complexes during XCI. Moreover, a series of features associated with active transcriptional elongation and chromatin 3D structure are enriched at rapidly silenced genes. Our machine-learning approach can thus uncover the complex combinatorial rules underlying gene silencing during X inactivation.

SUBMITTER: Barros de Andrade E Sousa L

PROVIDER: S-EPMC6633258 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acetogens are anaerobic bacteria capable of fixing CO2 or CO to produce acetyl coenzyme A (acetyl-CoA) and ultimately acetate using the Wood-Ljungdahl pathway (WLP). Acetobacterium woodii is the type strain of the Acetobacterium genus and has been critical for understanding the biochemistry and energy conservation in acetogens. Members of the Acetobacterium genus have been isolated from a variety of environments or have had genomes recovered from metagenome data, but no systematic investigation has been done on the unique and various metabolisms of the genus. To gain a better appreciation for the metabolic breadth of the genus, we sequenced the genomes of 4 isolates (A. fimetarium, A. malicum, A. paludosum, and A. tundrae) and conducted a comparative genome analysis (pan-genome) of 11 different Acetobacterium genomes. A unifying feature of the Acetobacterium genus is the carbon-fixing WLP. The methyl (cluster II) and carbonyl (cluster III) branches of the Wood-Ljungdahl pathway are highly conserved across all sequenced Acetobacterium genomes, but cluster I encoding the formate dehydrogenase is not. In contrast to A. woodii, all but four strains encode two distinct Rnf clusters, Rnf being the primary respiratory enzyme complex. Metabolism of fructose, lactate, and H2:CO2 was conserved across the genus, but metabolism of ethanol, methanol, caffeate, and 2,3-butanediol varied. Additionally, clade-specific metabolic potential was observed, such as amino acid transport and metabolism in the psychrophilic species, and biofilm formation in the A. wieringae clade, which may afford these groups an advantage in low-temperature growth or attachment to solid surfaces, respectively.IMPORTANCE Acetogens are anaerobic bacteria capable of fixing CO2 or CO to produce acetyl-CoA and ultimately acetate using the Wood-Ljungdahl pathway (WLP). This autotrophic metabolism plays a major role in the global carbon cycle and, if harnessed, can help reduce greenhouse gas emissions. Overall, the data presented here provide a framework for examining the ecology and evolution of the Acetobacterium genus and highlight the potential of these species as a source for production of fuels and chemicals from CO2 feedstocks.

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Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features.

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