Silencing Surprise

A chromatin remodeler in embryonic stem cells clears the DNA for mRNA transcription while stifling the expression of noncoding transcripts.

By | June 1, 2015

BAF BLOCKER: In normal embryonic stem cells (top panel), the chromatin remodeling complex esBAF moves nucleosomes into enhancer-flanking DNA regions (blue) to keep enhancers (red) free of nucleosomes so they can promote transcription of protein-coding genes. When esBAF is absent (lower panel), nucleosomes move out of the flanking regions and into the enhancer, freeing up noncoding RNA transcription that begins in the enhancer and continues into the flanking DNA.© SCOTT LEIGHTON

EDITOR'S CHOICE IN GENETICS & GENOMICS

The paper
S.J. Hainer et al., “Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF,” Genes & Development, 29:362-78, 2015.

To stuff more than six feet of DNA into the nucleus of each cell in our body, the genome winds tightly around a core of eight histone proteins, creating structures called nucleosomes that, in turn, are densely packed into chromatin. To transcribe genetic information from DNA to RNA, nucleosomes must be shifted out of the way, a task performed in some cases by the embryonic stem cell chromatin remodeling complex esBAF. This process opens up not just the region of DNA to be transcribed, but promoters and enhancers that encourage transcription.

Recent genome-sequencing work has revealed that enhancer regions not only promote the transcription of protein-coding genes, but can also contain the script for noncoding RNAs. Although noncoding RNAs are a hot topic, how they are regulated isn’t understood, says Toshio Tsukiyama of the University of Washington.

Thomas Fazzio, a former graduate student of Tsukiyama who is now an assistant professor at the University of Massachusetts Medical School, wanted to understand how the positioning of nucleosomes near enhancers might regulate noncoding RNA transcribed from the enhancer region. “We thought it was almost obvious that if BAF is important for keeping the chromatin structure of lots of enhancers open,” it would support the transcription of noncoding RNAs from those genomic stretches as well, he says. Yet when Fazzio and his colleagues sequenced the RNA from esBAF knockdown mouse embryonic stem cells, they found that noncoding RNAs from approximately 57,000 genomic regions were expressed at higher levels than in the control. The effect was not seen in more-differentiated mouse embryonic fibroblasts.

To further explore the unexpected finding, the researchers treated the DNA with an enzyme that only cuts in nucleosome-free regions and sequenced the fragments to determine the nucleosomes’ locations. Enhancer regions of esBAF knockout cells were covered by nucleosomes, but there were far fewer nucleosomes in flanking regions, suggesting that esBAF increases the nucleosome occupancy there. Adding DNA sequences that lock nucleosomes in place at both sides of the enhancer repressed the noncoding transcripts, even without esBAF. “I was really impressed that using mammalian cells they actually...directly show that it is really the nucleosome occupancy that matters for noncoding RNA regulation,” says Tsukiyama, who did not participate in the experiments.

The results point “to the intricacies of how [chromatin remodeling] complexes are used by the cell,” says Swaminathan Venkatesh of the Stowers Institute for Medical Research in Kansas City, Missouri, who was not involved in the study. “A complex that has traditionally been viewed to be involved in activating transcription is actually repressing noncoding transcripts.”

It’s not clear how important the repression of noncoding transcripts is for pluripotency, Fazzio says. There are many long noncoding RNAs implicated in differentiation, says Venkatesh, and “you can imagine that suppressing them in embryonic stem cells is preventing differentiation from taking place.”

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Avatar of: James V. Kohl

James V. Kohl

Posts: 460

June 11, 2015

Excerpt: "The results point “to the intricacies of how [chromatin remodeling] complexes are used by the cell,” says Swaminathan Venkatesh of the Stowers Institute for Medical Research in Kansas City, Missouri, who was not involved in the study. “A complex that has traditionally been viewed to be involved in activating transcription is actually repressing noncoding transcripts.”

My comment: There are too many surprises to continue accepting any prior representations that attempted to link mutations and/or natural selection to the evolution of cell type differences in all genera. Simply put, the theorists believed in theories, not facts about biologically-based cell type differentiation, which is nutrient-dependent and controlled by the physiology of reproduction in the context of RNA-mediated events.

Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems

Avatar of: James V. Kohl

James V. Kohl

Posts: 460

June 11, 2015

See also:

From Fertilization to Adult Sexual Behavior

Excerpt: The Genome, positioning, timings. There are major structural differences between the X and Y chromosomes; e.g., centromeric aiphoid repeats sequences and distribution of heterochromatin (Graves, 1995; Wolfe et al., 1985). These structural differences correlate with sexually dimorphic chromosomal positioning within the nucleus and with male/female differences in replication timing of the active X, the inactive X, and the Y chromosomes, e.g., Boggs and Chinault (1994), Clemson and Lawrence (1996); Hansen, Canfield, and Gartler (1995). Increasingly the structure and timings within the nucleus are realized as contributing to gene expression regulation (Manders, Stap, Strackee, van Driel, and Aten, 1996; Stein, Stein, Lian, van Wijnen, and Montecino, 1996).

My comment:

The molecular mechanisms of cell type differentiation have since been extended to all cell types in all individuals of all genera via what is known about RNA-directed DNA methylation and RNA-mediated amino acid substitutions that stabilize organized genomes.

Avatar of: James V. Kohl

James V. Kohl

Posts: 460

June 11, 2015

Human body epigenome maps reveal noncanonical DNA methylation variation

Abstract excerpt:

Overall, DNA methylation in several genomic contexts varies substantially among human tissues.

If RNA-directed DNA methylation did not link thermodynamic cycles of nutrient-dependent protein biosynthesis and degradation to the stability of organized genomes via RNA-mediated amino acid substitutions, how could organism-level thermoregulation establish a link between the epigenetic landscape and the physical landscape of DNA in all genera?

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