Past Roadblocks and New Opportunities in Transcription Factor Network Mapping

Brent, Michael R.

doi:10.1016/j.tig.2016.08.009

Cited by 24 publications

(23 citation statements)

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“…Section 2.3.3. and Section 2.3.4.; Figure S17). Alternatively, the observed stereotypical patterns of TF binding might indicate non-specific “phantom peaks” due to high level transcription of the corresponding regulatory elements [68,147]. Site-directed mutagenesis studies will be necessary to demonstrate the functional role of these elements.…”

Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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“…Cell type is thought to be controlled through the activity of transcription factors (TFs), that respond to either internal or external cellular cues. 59 TFs bind to DNA and regulate gene expression, and interact with local chromatin to control cell type. Although a comprehensive model describing exactly how TFs perform these feats remains frustratingly elusive.…”

Section: Transcriptional Control Of Cell Typementioning

confidence: 99%

Genomic and molecular control of cell type and cell type conversions

et al. 2017

Cell Regeneration

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Organisms are made of a limited number of cell types that combine to form higher order tissues and organs. Cell types have traditionally been defined by their morphologies or biological activity, yet the underlying molecular controls of cell type remain unclear. The onset of single cell technologies, and more recently genomics (particularly single cell genomics), has substantially increased the understanding of the concept of cell type, but has also increased the complexity of this understanding. These new technologies have added a new genome wide molecular dimension to the description of cell type, with genome-wide expression and epigenetic data acting as a cell type ‘fingerprint’ to describe the cell state. Using these genomic fingerprints cell types are being increasingly defined based on specific genomic and molecular criteria, without necessarily a distinct biological function. In this review, we will discuss the molecular definitions of cell types and cell type control, and particularly how endogenous and exogenous transcription factors can control cell types and cell type conversions.

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“…The results show that NetProphet is more accurate than a simple LASSO regression approach, which is more accurate than CLR, consistent with our previously published comparison of these algorithms (14) (see ref. 27 for a recent review of TF network mapping algorithms.) As expected, scoring potential TF-target relations by the correlation of the TF's expression level with target's expression level performed worse than CLR, which postprocesses correlation coefficients.…”

Section: −5mentioning

confidence: 99%

Model-based transcriptome engineering promotes a fermentative transcriptional state in yeast

Michael

Maier

Brown

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ability to rationally manipulate the transcriptional states of cells would be of great use in medicine and bioengineering. We have developed an algorithm, NetSurgeon, which uses genomewide gene-regulatory networks to identify interventions that force a cell toward a desired expression state. We first validated NetSurgeon extensively on existing datasets. Next, we used NetSurgeon to select transcription factor deletions aimed at improving ethanol production in Saccharomyces cerevisiae cultures that are catabolizing xylose. We reasoned that interventions that move the transcriptional state of cells using xylose toward that of cells producing large amounts of ethanol from glucose might improve xylose fermentation. Some of the interventions selected by NetSurgeon successfully promoted a fermentative transcriptional state in the absence of glucose, resulting in strains with a 2.7-fold increase in xylose import rates, a 4-fold improvement in xylose integration into central carbon metabolism, or a 1.3-fold increase in ethanol production rate. We conclude by presenting an integrated model of transcriptional regulation and metabolic flux that will enable future efforts aimed at improving xylose fermentation to prioritize functional regulators of central carbon metabolism.gene-regulatory networks | regulatory systems biology | transcriptome | engineering | Saccharomyces cerevisiae T he central premise of regulatory systems biology is that a systematic map of a cell's regulatory machinery will enable us to understand, predict, and rationally manipulate the cell's state or behavior. Manipulation of cellular state has many promising applications, including stem cell biology and regenerative medicine, biofuel production, and gene therapy. Progress toward cellular state control has been driven by both the systems biology and the synthetic biology research communities. Systems biology has produced whole-genome regulatory network maps (1), but relatively little research has focused on using these maps for predicting and manipulating cellular behavior (2). Regulatory synthetic biology has focused on creating molecular circuits that can be placed into a cell to control the transcription of a small number of transgenes, but genome-scale engineering of the cell's native regulatory apparatus is still rare, with most systems restricted to a limited set of controlled targets (3). Here, we demonstrate that transcription factor (TF) network mapping, gene expression profiling, and computational modeling can be integrated to rationally engineer transcriptional state. We call this activity, which bridges the gap between systems biology and synthetic biology, "transcriptome engineering

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Past Roadblocks and New Opportunities in Transcription Factor Network Mapping

Cited by 24 publications

References 100 publications

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Genomic and molecular control of cell type and cell type conversions

Model-based transcriptome engineering promotes a fermentative transcriptional state in yeast

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