regulatory circuit
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2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Romain Girard ◽  
Sarah Tremblay ◽  
Christophe Noll ◽  
Stéphanie St-Jean ◽  
Christine Jones ◽  
...  

AbstractThe transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Peter Fabian ◽  
Kuo-Chang Tseng ◽  
Mathi Thiruppathy ◽  
Claire Arata ◽  
Hung-Jhen Chen ◽  
...  

AbstractThe cranial neural crest generates a huge diversity of derivatives, including the bulk of connective and skeletal tissues of the vertebrate head. How neural crest cells acquire such extraordinary lineage potential remains unresolved. By integrating single-cell transcriptome and chromatin accessibility profiles of cranial neural crest-derived cells across the zebrafish lifetime, we observe progressive and region-specific establishment of enhancer accessibility for distinct fates. Neural crest-derived cells rapidly diversify into specialized progenitors, including multipotent skeletal progenitors, stromal cells with a regenerative signature, fibroblasts with a unique metabolic signature linked to skeletal integrity, and gill-specific progenitors generating cell types for respiration. By retrogradely mapping the emergence of lineage-specific chromatin accessibility, we identify a wealth of candidate lineage-priming factors, including a Gata3 regulatory circuit for respiratory cell fates. Rather than multilineage potential being established during cranial neural crest specification, our findings support progressive and region-specific chromatin remodeling underlying acquisition of diverse potential.


2022 ◽  
Vol 23 (2) ◽  
pp. 611
Author(s):  
Chiara Siniscalchi ◽  
Armando Di Palo ◽  
Aniello Russo ◽  
Nicoletta Potenza

Non-coding RNAs (ncRNAs) constitute the majority of the transcriptome, as the result of pervasive transcription of the mammalian genome. Different RNA species, such as lncRNAs, miRNAs, circRNA, mRNAs, engage in regulatory networks based on their reciprocal interactions, often in a competitive manner, in a way denominated “competing endogenous RNA (ceRNA) networks” (“ceRNET”): miRNAs and other ncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs, titrating their availability and thus competing with the binding to other RNA targets. The unbalancing of any network component can derail the entire regulatory circuit acting as a driving force for human diseases, thus assigning “new” functions to “old” molecules. This is the case of XIST, the lncRNA characterized in the early 1990s and well known as the essential molecule for X chromosome inactivation in mammalian females, thus preventing an imbalance of X-linked gene expression between females and males. Currently, literature concerning XIST biology is becoming dominated by miRNA associations and they are also gaining prominence for other lncRNAs produced by the X-inactivation center. This review discusses the available literature to explore possible novel functions related to ceRNA activity of lncRNAs produced by the X-inactivation center, beyond their role in dosage compensation, with prospective implications for emerging gender-biased functions and pathological mechanisms.


Author(s):  
Na Zhao ◽  
Haihong Liu ◽  
Fang Yan

Bacillus subtilis with competent states absorbs DNA and may improve the growth of bacteria by integrating new genetic material. Therefore, it is important to clarify how the genes interact in the circuit so that cells enter into a competent state or return to a vegetative state. The gene regulatory circuit consists of two positive feedback loops and one negative feedback loop. In this paper, a mathematical model is developed by considering transcription time delays to further study dynamic behavior of the B. subtilis competent gene regulatory network. Combined with theoretical calculation and numerical simulation, it is verified that the time delay in indirect transcription inhibition indeed has the effect of inducing the periodic oscillation of the B. subtilis competent system. In addition, some important chemical reaction rates can also regulate system dynamic behavior. However, under the control of time delay, the effects of the important chemical reaction rates have changed significantly. In particular, the time delay can advance critical value of the important chemical reaction rates where vibration occurs and can also weaken or even eliminate the effect of the important chemical reaction rates. These results will help us to analyze the competent state of B. subtilis.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Qiuling Li ◽  
Hyunsoo Jang ◽  
Kayla Y Lim ◽  
Alexie Lessing ◽  
Nicholas Stavropoulos

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here we show that Insomniac (Inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body, a center for sensory integration, associative learning, and sleep regulation. In inc mutants, mushroom body neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.


2021 ◽  
Author(s):  
Cise Kizilirmak ◽  
Emanuele Monteleone ◽  
Jose M. Garcia-Manteiga ◽  
Francesca Brambilla ◽  
Alessandra Agresti ◽  
...  

Transcription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at single-cell level. The source of this dynamic variability is not completely understood. Here we focus on the nuclear factor κB (NF-κB), whose dynamics have been reported to cover a wide spectrum ranging from oscillatory to non-oscillatory. We show that clonal populations of immortalized fibroblasts derived from a single mouse embryo (that can hence be considered quasi-identical) display robustly distinct dynamics upon tumor necrosis α (TNF-α) stimulation. Combining transcriptomics, data-constrained mathematical modelling, and mRNA interference we show that small differences in the expression of genes belonging to the NF-κB regulatory circuit are predictive of the distinct responses to inflammatory stimuli observed among the clones. We propose that this transcriptional fine-tuning can be a general mechanism to produce cell subpopulations with distinct dynamic responses to stimuli within homogeneous cell populations.


2021 ◽  
Author(s):  
Andreas Damianou ◽  
Zhu Liang ◽  
Benedikt M Kessler ◽  
Frederik Lassen ◽  
George Vere ◽  
...  

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute up to 30% of human solid tumours including lung adenocarcinoma, pancreatic and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. Here, APEX-2 proximity labelling was used to profile the molecular environment of wild type and G12D, G13D and Q61H activating mutants of KRAS under both, starvation and stimulation conditions. We demonstrate by quantitative proteomics the presence of known interactors of KRAS including a-RAF and LZTR1, which varied in abundance with wildtype and KRAS mutants. Notably, the KRAS mutations G12D, G13D and Q61H abrogate association with LZTR1. Wildtype KRAS and LZTR1, as part of the CUL3 ubiquitin E3 ligase complex, affect each other's protein stability, revealing a direct feedback loop mechanism. KRAS mutations disconnect this regulatory circuit, thereby contributing to oncogenesis.


2021 ◽  
Vol 12 ◽  
Author(s):  
Disha Bhange ◽  
Nityanand Prasad ◽  
Swati Singh ◽  
Harshit Kumar Prajapati ◽  
Shesh Prakash Maurya ◽  
...  

In a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not the coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but no significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a coinfection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Davy Deng ◽  
Frank Dubois ◽  
Alexander Crane ◽  
Ashot Harutyunyan ◽  
Rameen Beroukhim ◽  
...  

Abstract BACKGROUND Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind. METHOD Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs. RESULTS We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene. CONCLUSION We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.


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