Differences in evolutionary accessibility determine which equally effective regulatory motif evolves to generate pulses

Expression Levels ◽

Negative Feedback Loops ◽

Selection For ◽

Relative Functionality

Abstract Transcriptional regulatory networks (TRNs) are enriched for certain “motifs”. Motif usage is commonly interpreted in adaptationist terms, i.e. that the optimal motif evolves. But certain motifs can also evolve more easily than others. Here, we computationally evolved TRNs to produce a pulse of an effector protein. Two well-known motifs, type 1 incoherent feed-forward loops (I1FFLs) and negative feedback loops (NFBLs), evolved as the primary solutions. The relative rates at which these two motifs evolve depend on selection conditions, but under all conditions, either motif achieves similar performance. I1FFLs generally evolve more often than NFBLs. Selection for a tall pulse favors NFBLs, while selection for a fast response favors I1FFLs. I1FFLs are more evolutionarily accessible early on, before the effector protein evolves high expression; when NFBLs subsequently evolve, they tend to do so from a conjugated I1FFL-NFBL genotype. In the empirical S. cerevisiae TRN, output genes of NFBLs had higher expression levels than those of I1FFLs. These results suggest that evolutionary accessibility, and not relative functionality, shapes which motifs evolve in TRNs, and does so as a function of the expression levels of particular genes.

Non-adaptive factors determine which equally effective regulatory motif evolves to generate pulses

10.1101/2020.12.02.409151 ◽

2020 ◽

Author(s):

Kun Xiong ◽

Mark Gerstein ◽

Joanna Masel

Keyword(s):

Regulatory Networks ◽

De Novo ◽

Superior Performance ◽

Network Motifs ◽

Expression Levels ◽

Negative Feedback Loops ◽

Relative Functionality

AbstractTranscriptional regulatory networks (TRNs) are enriched for certain subnetworks or “motifs”. Motif usage is commonly interpreted as the result of adaptive evolution. But network motifs can also differ in how easy it is to evolve them. Here, we simulated the de novo evolution of motifs within TRNs under selection to produce a short, sharp pulse of an effector protein. In agreement with past work in the field, two network motifs, type 1 incoherent feed-forward loops (I1FFLs) and negative feedback loops (NFBLs), evolved as the primary solutions. Different selection conditions changed the relative frequencies of the two solutions, but this was not due to the superior performance of one; under all conditions, either motif can achieve similar top performance. I1FFLs generally evolve more often than NFBLs, unless we selected for a particularly tall pulse. This result suggests that I1FFLs are evolutionary more accessible than NFBLs. When NFBLs do evolve, it is usually from a conjugate containing both I1FFL and NFBL. In contrast, I1FFLs can evolve via a greater variety of trajectories. This difference potentially explains NFBL’s lower evolutionary accessibility. To agreement with our simulation results, we found that in the real yeast TRN, output genes of NFBLs had higher expression levels than those of I1FFLs, i.e. selection for taller pulses. These results suggest that evolutionary accessibility, and not relative functionality, shape which networks motifs evolve in TRNs, and do so as a function of the expression levels of particular genes.

Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

10.1101/465435 ◽

2018 ◽

Cited By ~ 1

Author(s):

Maria Pokrovskii ◽

Jason A. Hall ◽

David E. Ochayon ◽

Ren Yi ◽

Natalia S. Chaimowitz ◽

...

Keyword(s):

Regulatory Networks ◽

Inflammatory Diseases ◽

Innate Lymphoid Cells ◽

Chromatin Accessibility ◽

Immune Defense ◽

Lymphoid Cells ◽

Transcriptional Regulatory

SummaryInnate lymphoid cells (ILCs) can be subdivided into several distinct cytokine-secreting lineages that promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Accumulating evidence suggests that ILCs, similarly to other immune populations, are capable of phenotypic and functional plasticity in response to infectious or environmental stimuli. Yet the transcriptional circuits that control ILC identity and function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer transcriptional regulatory networks within intestinal type 1, 2, and 3 ILCs. We predict the “core” sets of transcription-factor (TF) regulators driving each ILC subset identity, among which only a few TFs were previously known. To assist in the interpretation of these networks, TFs were organized into cooperative clusters, or modules that control gene programs with distinct functions. The ILC network reveals extensive alternative-lineage-gene repression, whose regulation may explain reported plasticity between ILC subsets. We validate new roles for c-MAF and BCL6 as regulators affecting the type 1 and type 3 ILC lineages. Manipulation of TF pathways identified here might provide a novel means to selectively regulate ILC effector functions to alleviate inflammatory disease or enhance host tolerance to pathogenic microbes or noxious stimuli. Our results will enable further exploration of ILC biology, while our network approach will be broadly applicable to identifying key cell state regulators in otherin vivocell populations.

Faculty Opinions recommendation of Transcriptional regulatory networks in epiblast cells and during anterior neural plate development as modeled in epiblast stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717961063.793463869 ◽

2012 ◽

Author(s):

Patrick Tam

Keyword(s):

Stem Cells ◽

Regulatory Networks ◽

Neural Plate ◽

Epiblast Stem Cells ◽

Anterior Neural Plate

Transcriptional Regulatory Networks Involved in C3–C4 Alcohol Stress Response and Tolerance in Yeast

ACS Synthetic Biology ◽

10.1021/acssynbio.0c00253 ◽

2020 ◽

Author(s):

Liya Liang ◽

Rongming Liu ◽

Emily F. Freed ◽

Carrie A. Eckert ◽

Ryan T. Gill

Keyword(s):

Stress Response ◽

Regulatory Networks ◽

Transcriptional Regulatory

Transcriptional Control of Parturition: Insights from Gene Regulation Studies in the Myometrium

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaab024 ◽

2021 ◽

Author(s):

Nawrah Khader ◽

Virlana M Shchuka ◽

Oksana Shynlova ◽

Jennifer A Mitchell

Keyword(s):

Transcription Factors ◽

Regulatory Networks ◽

Transcriptional Control ◽

Progesterone Receptors ◽

Activator Protein 1 ◽

Regulatory Pathways ◽

Mechanistic Basis ◽

Labour Onset

Abstract The onset of labour is a culmination of a series of highly coordinated and preparatory physiological events that take place throughout the gestational period. In order to produce the associated contractions needed for fetal delivery, smooth muscle cells in the muscular layer of the uterus (i.e. myometrium) undergo a transition from quiescent to contractile phenotypes. Here, we present the current understanding of the roles transcription factors play in critical labour-associated gene expression changes as part of the molecular mechanistic basis for this transition. Consideration is given to both transcription factors that have been well-studied in a myometrial context, i.e. activator protein 1 (AP-1), progesterone receptors (PRs), estrogen receptors (ERs), and nuclear factor kappa B (NF-κB), as well as additional transcription factors whose gestational event-driving contributions have been demonstrated more recently. These transcription factors may form pregnancy- and labour- associated transcriptional regulatory networks in the myometrium to modulate the timing of labour onset. A more thorough understanding of the transcription factor-mediated, labour-promoting regulatory pathways holds promise for the development of new therapeutic treatments that can be used for the prevention of preterm labour in at-risk women.

Transcriptional Regulatory Networks Associate with Early Stages of Potato Virus X Infection of Solanum tuberosum

International Journal of Molecular Sciences ◽

10.3390/ijms22062837 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2837

Author(s):

Venura Herath ◽

Jeanmarie Verchot

Keyword(s):

Potato Virus ◽

Regulatory Networks ◽

Potato Virus X ◽

Early Response ◽

Pathogen Resistance ◽

Unfolded Protein ◽

Molecular Pattern ◽

Protein Response

Potato virus X (PVX) belongs to genus Potexvirus. This study characterizes the cellular transcriptome responses to PVX infection in Russet potato at 2 and 3 days post infection (dpi). Among the 1242 differentially expressed genes (DEGs), 268 genes were upregulated, and 37 genes were downregulated at 2 dpi while 677 genes were upregulated, and 265 genes were downregulated at 3 dpi. DEGs related to signal transduction, stress response, and redox processes. Key stress related transcription factors were identified. Twenty-five pathogen resistance gene analogs linked to effector triggered immunity or pathogen-associated molecular pattern (PAMP)-triggered immunity were identified. Comparative analysis with Arabidopsis unfolded protein response (UPR) induced DEGs revealed genes associated with UPR and plasmodesmata transport that are likely needed to establish infection. In conclusion, this study provides an insight on major transcriptional regulatory networked involved in early response to PVX infection and establishment.

The nuclear receptor HNF4 drives a brush border gene program conserved across murine intestine, kidney, and embryonic yolk sac

Nature Communications ◽

10.1038/s41467-021-22761-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lei Chen ◽

Shirley Luo ◽

Abigail Dupre ◽

Roshan P. Vasoya ◽

Aditya Parthasarathy ◽

...

Keyword(s):

Brush Border ◽

Regulatory Networks ◽

Critical Role ◽

Yolk Sac ◽

Apical Surface ◽

Chromatin Looping ◽

Multiple Organs ◽

Transcriptional Regulatory Mechanisms

AbstractThe brush border is comprised of microvilli surface protrusions on the apical surface of epithelia. This specialized structure greatly increases absorptive surface area and plays crucial roles in human health. However, transcriptional regulatory networks controlling brush border genes are not fully understood. Here, we identify that hepatocyte nuclear factor 4 (HNF4) transcription factor is a conserved and important regulator of brush border gene program in multiple organs, such as intestine, kidney and yolk sac. Compromised brush border gene signatures and impaired transport were observed in these tissues upon HNF4 loss. By ChIP-seq, we find HNF4 binds and activates brush border genes in the intestine and kidney. H3K4me3 HiChIP-seq identifies that HNF4 loss results in impaired chromatin looping between enhancers and promoters at gene loci of brush border genes, and instead enhanced chromatin looping at gene loci of stress fiber genes in the intestine. This study provides comprehensive transcriptional regulatory mechanisms and a functional demonstration of a critical role for HNF4 in brush border gene regulation across multiple murine epithelial tissues.