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Transcription factors read epigenetics

Science

Decoding precisely how sequence-specific DNA binding proteins (called transcription factors) recognize, access, and act at their genomic binding sites is challenging. One shortcoming is the lack of knowledge about DNA binding specificities (motifs) for hundreds of the estimated 1600 human transcription factors. Another is how transcription factor binding is modulated by "epigenetics"--a contentious term that refers to heritable states of both cells and organisms, as well as the covalent chemical modifications of DNA and protein that often provide the underlying mechanism (1). DNA methylation at cytosine and guanine dinucleotides (mCG) satisfies most views of epigenetics, as it is inherited across cell divisions and functions in imprinting (parent-of-origin-dependent gene expression). On page 502 of this issue, Yin et al. (2) provide a comprehensive look at the extent to which human transcription factor binding is affected by mCG, and make a striking finding: Many homeodomain transcription factors--perhaps the best-characterized developmental regulators in biology (3)--can bind to specific methylated DNA sequences.


Synthetic transcription elongation factors license transcription across repressive chromatin

Science

The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy.


Rev-erb{alpha} dynamically modulates chromatin looping to control circadian gene transcription

Science

Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors that constitute molecular clocks. Core clock transcription factors bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. We found that in mice, circadian gene expression in the liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive transcription factor of the clock, opposes functional loop formation between Rev-erbα–regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 co-repressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.


Overfed mice got rhythm

Science

Metabolic health is intertwined with the body's circadian clock, but the mechanisms underlying this connection are not fully understood. Studying mice, Guan et al. examined the effect of diet-induced obesity on circadian expression of genes in the liver. They found that obesity intensifies and synchronizes the liver circadian rhythms of enhancers that control the expression of two transcription factors with opposing effects on lipid metabolism. The result is enhanced synthesis and oxidation of fatty acids. Drugs activating one of these transcription factors, PPARα, are already used clinically to reduce lipid levels.


1016.4?rss=1

Science

In embryonic development and growth control, the histone acetyltransferase p300/CBP (CBP) serves as a transcriptional coactivator with hundreds of different partner transcription factors. By examining the role of CBP in fruitfly cells, Boija et al. have extended its functional repertoire in regulating gene expression. Promoters cobound with CBP and GAGA factor were among the most highly expressed and displayed the most highly paused polymerase (Pol) II. CBP kept Pol II in the stalled position but also aided subsequent transcription elongation through release at the first downstream nucleosome. In addition, CBP and the general transcription factor TFIIB recruited Pol II to the promoter. These CBP activities clarify the mechanism by which the ubiquitous CBP factor does its job as transcriptional coactivator for many cell processes.