A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators

Hurst, Laurence D.; Sachenkova, Oxana; Daub, Carsten O.; Forrest, Alistair R.R.; Huminiecki, Łukasz

doi:10.1186/preaccept-7285495961101327

Cited by 12 publications

(35 citation statements)

References 32 publications

(42 reference statements)

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“…We further speculate that this mechanism is also involved in gene repression during other transitions like cellular differentiation, which would be consistent with the notion that most mammalian transcription factors are activating (Hurst et al 2014).…”

Section: Tnf-induced Adipocyte Inflammationsupporting

confidence: 89%

Modulating the Genomic Programming of Adipocytes

Loft

Schmidt

Mandrup

2015

Cold Spring Harb Symp Quant Biol

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The ability to modify the transcriptional program in response to external signals provides a way for mammalian cells to alter their biological fate and properties, thereby adapting to changes in the environment. Adipocytes are excellent examples of differentiated cells that possess a striking transcriptional plasticity when exposed to physiological and metabolic stimuli. In our work, we have focused on understanding the processes responsible for modulating the genomic programming in response to different external signals. Thus, we have shown that browning of human adipocytes with rosiglitazone, an antidiabetic agonist of the key adipocyte transcription factor peroxisome proliferator-activated receptor g (PPARg), involves redistribution of PPARg binding to form browning-selective PPARg super-enhancers that drive expression of key browning genes. These include genes encoding transcriptional regulators, such as Krüppel-like factor 11 (KLF11) that are essential for modulating the genomic program in white adipocytes to induce browning. Furthermore, we have shown that acute suppression of adipocyte genes by the proinflammatory cytokine, tumor necrosis factor (TNF), involves redistribution of cofactors to enhancers activated by the master inflammatory regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Interestingly, this redistribution occurs selectively from enhancers with high-cofactor occupancies, thereby predominantly affecting super-enhancers and their associated genes. We propose that this is a general mechanism contributing to transcriptional repression associated with activation of signal-dependent transcription factors.

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Section: Tnf-induced Adipocyte Inflammationsupporting

confidence: 89%

Modulating the Genomic Programming of Adipocytes

Loft

Schmidt

Mandrup

2015

Cold Spring Harb Symp Quant Biol

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“…A complete list of this dataset is available at Additional file 1 : Table S1. Since many reports have also used a window that flanks the TSS of known genes [ 16 , 17 ], we have also defined a different window of same size (5 KB) now encompassing 2,5 KB in each side of a given TSS. For this window, we found that 9,733 human genes had at least one TFBS affected by a polymorphic INDEL in the 1000 Genomes dataset (with a total of 69,959 TFBS affected by indels and 14,665 TFBS-ID).…”

Section: Resultsmentioning

confidence: 99%

Populational landscape of INDELs affecting transcription factor-binding sites in humans

et al. 2015

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BackgroundDifferences in gene expression have a significant role in the diversity of phenotypes in humans. Here we integrated human public data from ENCODE, 1000 Genomes and Geuvadis to explore the populational landscape of INDELs affecting transcription factor-binding sites (TFBS). A significant fraction of TFBS close to the transcription start site of known genes is affected by INDELs with a consequent effect at the expression of the associated gene.ResultsHundreds of TFBS-affecting INDELs (TFBS-ID) show a differential frequency between human populations, suggesting a role of natural selection in the spread of such variant INDELs. A comparison with a dataset of known human genomic regions under natural selection allowed us to identify several cases of TFBS-ID likely involved in populational adaptations. Ontology analyses on the differential TFBS-ID further indicated several biological processes under natural selection in different populations.ConclusionTogether, our results strongly suggest that INDELs have an important role in modulating gene expression patterns in humans. The dataset we make available, together with other data reporting variability at both regulatory and coding regions of genes, represent a powerful tool for studies aiming to better understand the evolution of gene regulatory networks in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1744-5) contains supplementary material, which is available to authorized users.

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“…A correlation between the size of promoter architecture and the breadth of expression was detected. Transcription factors with the strongest contribution to housekeeping expression were identified [ 10,11] Anti-reductionist Signaling pathway (33 animal genomes were surveyed)…”

Section: Strategymentioning

confidence: 99%

A Contemporary Message from Mendel's Logical Empiricism

Huminiecki

2020

BioEssays

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The gene is one of the most fundamental concepts in life sciences, having been developed in the mold of the Mendelian paradigm of heredity, which shaped genetics across 150 years. How could Mendel possibly be so prophetic in the middle of 19th century, using only the small garden of the monastery as his experimental breeding field? I believe that we are indebted to Mendel's mastery of the scientific method, which was far ahead of his time. Although his experimental technology was literally garden‐variety, Mendel's excellence in the method of science, algebra, and logical analysis helped him in designing the right experiment and in interpreting the results insightfully. This may be valuable to recall in today's technology‐focused culture, where the center of interest tends to be on the generation and description of high‐throughput datasets from specialized genomics screens. As Mendel's story suggests, progress in 21st century genetics may also depend on the development of robust concepts and generalizations.

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A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators

Cited by 12 publications

References 32 publications

Modulating the Genomic Programming of Adipocytes

Modulating the Genomic Programming of Adipocytes

Populational landscape of INDELs affecting transcription factor-binding sites in humans

A Contemporary Message from Mendel's Logical Empiricism

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