Gene Regulation: When Analog Beats Digital

Lorberbaum, David S.; Barolo, Scott

doi:10.1016/j.cub.2013.10.004

Cited by 10 publications

(11 citation statements)

References 21 publications

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“…This may be a more adequate approximation to some genes than others, where ‘analogue’ regulation by fine-tuning expression levels may be more relevant. The digital and analogue views are also not mutually exclusive and a more careful exploration of the mechanistic basis and biological function of these two modes would greatly benefit the community [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Haematopoietic stem cells: entropic landscapes of differentiation

Wiesner¹,

Teles

Hartnor

et al. 2018

Interface Focus.

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The metaphor of a potential epigenetic differentiation landscape broadly suggests that during differentiation a stem cell approaches a stable equilibrium state from a higher free energy towards a stable equilibrium state which represents the final cell type. It has been conjectured that there is an analogy to the concept of entropy in statistical mechanics. In this context, in the undifferentiated state, the entropy would be large since fewer constraints exist on the gene expression programmes of the cell. As differentiation progresses, gene expression programmes become more and more constrained and thus the entropy would be expected to decrease. In order to assess these predictions, we compute the Shannon entropy for time-resolved single-cell gene expression data in two different experimental set-ups of haematopoietic differentiation. We find that the behaviour of this entropy measure is in contrast to these predictions. In particular, we find that the Shannon entropy is not a decreasing function of developmental pseudo-time but instead it increases towards the time point of commitment before decreasing again. This behaviour is consistent with an increase in gene expression disorder observed in populations sampled at the time point of commitment. Single cells in these populations exhibit different combinations of regulator activity that suggest the presence of multiple configurations of a potential differentiation network as a result of multiple entry points into the committed state.

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Section: Discussionmentioning

confidence: 99%

Haematopoietic stem cells: entropic landscapes of differentiation

Wiesner¹,

Teles

Hartnor

et al. 2018

Interface Focus.

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“…Thus, there is a large reservoir of available CUX1 binding sites that are unoccupied. This suggests that the number of potential CUX1 binding sites outnumbers the available CUX1 protein in the cell, and CUX1 genomic occupancy remains unsaturated, a feature of analog TFs (18,19). …”

Section: Resultsmentioning

confidence: 99%

“…p200 CUX1 has low-affinity DNA binding (Figure 2 and ref. (15)), there is a large excess of unbound CUX1 binding sites, and there are multiple CUX1 binding sites at dose-sensitive genes (Figure 4C) (18–20). Collectively, these data argue against the affinity-threshold model, and in favor of the analog model of CUX1 gene regulation.…”

Section: Resultsmentioning

confidence: 99%

“…In the affinity-threshold model, target gene expression is ‘on’ or ‘off’ in a binary fashion. Other TFs ascribe to a linear or ‘analog’ gene regulation model, wherein target genes have graded transcriptional responses proportional to TF abundance (18–20). Linearity is associated with multiple TF binding sites per target gene, low-affinity TF binding, and an excess number of competing binding sites (18–20).…”

Section: Introductionmentioning

confidence: 99%

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The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters

Arthur

Khan

et al. 2017

Nucleic Acids Research

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One third of tumor suppressors are haploinsufficient transcriptional regulators, yet it remains unknown how a 50% reduction of a transcription factor is translated at the cis-regulatory level into a malignant transcriptional program. We studied CUX1, a haploinsufficient transcription factor that is recurrently mutated in hematopoietic and solid tumors. We determined CUX1 DNA-binding and target gene regulation in the wildtype and haploinsufficient states. CUX1 binds with transcriptional activators and cohesin at distal enhancers across three different human cell types. Haploinsufficiency of CUX1 altered the expression of a large number of genes, including cell cycle regulators, with concomitant increased cellular proliferation. Surprisingly, CUX1 occupancy decreased genome-wide in the haploinsufficient state, and binding site affinity did not correlate with differential gene expression. Instead, differentially expressed genes had multiple, low-affinity CUX1 binding sites, features of analog gene regulation. A machine-learning algorithm determined that chromatin accessibility, enhancer activity, and distance to the transcription start site are features of dose-sensitive CUX1 transcriptional regulation. Moreover, CUX1 is enriched at sites of DNA looping, as determined by Hi-C analysis, and these loops connect CUX1 to the promoters of regulated genes. We propose an analog model for haploinsufficient transcriptional deregulation mediated by higher order genome architecture.

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“…The dynamics of a gene's expression in a given cell can follow distinct kinetic models depending on gene function, cell type, and potentially, the homeostatic needs of the tissue. Some genes need to have a sharp on -off response when a stimulus threshold is reached (digital control), while others may utilize a more graded response where gene expression is proportional to the initial stimulus (analog control) (Lorberbaum and Barolo, 2013) (Figure 2A). As an example, for stress response genes such as NF-kB, a transcription factor involved in the control of inflammatory and immune responses, an analog and graded response is favorable in order to appropriately harmonize both inflammatory cues and cell responses (Giorgetti et al, 2010).…”

Section: Optimization Of Gene Expression For Transcriptional Therapeutics Component Dosage and Gene Expression Dynamicsmentioning

confidence: 99%

CRISPR-Based Synthetic Transcription Factors In Vivo: The Future of Therapeutic Cellular Programming

2020

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Pinpoint control over endogenous gene expression in vivo has long been a fevered dream for clinicians and researchers alike. With the recent repurposing of programmable, RNA-guided DNA endonucleases from the CRISPR bacterial immune system, this dream is becoming a powerful reality. Engineered CRISPR/Cas9based transcriptional regulators and epigenome editors have enabled researchers to perturb endogenous gene expression in vivo, allowing for the therapeutic reprogramming of cell and tissue behavior. For this technology to be of maximal use, a variety of technological hurdles still need to be addressed. Better understanding of the design principle controlling gene expression together with technologies that enable spatiotemporal control of transcriptional engineering are fundamental for rational design, improved efficacy, and ultimately safe translation to humans. In this review, we will discuss recent advances and integrative strategies that can help pave the path toward a new class of transcriptional therapeutics.

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Gene Regulation: When Analog Beats Digital

Abstract: Why do some genes seem to respond in a 'digital', on/off manner to a graded signal, while others produce an 'analog', graded response? A new study suggests that the DNA-binding properties of transcription factors can strongly influence the response patterns of gene networks.

Cited by 10 publications

References 21 publications

Haematopoietic stem cells: entropic landscapes of differentiation

Haematopoietic stem cells: entropic landscapes of differentiation

The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters

CRISPR-Based Synthetic Transcription Factors In Vivo: The Future of Therapeutic Cellular Programming

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