scholarly journals NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dalei Wu ◽  
Xiaoyu Su ◽  
Nalini Potluri ◽  
Youngchang Kim ◽  
Fraydoon Rastinejad
Keyword(s):  
Transcription Factors ◽  
Ligand Binding ◽  
Crystal Structures ◽  
Autism Spectrum ◽  
Helix Loop Helix ◽  
Aryl Hydrocarbon ◽  
Binding Pockets ◽  
Direct Targeting ◽  
Spectrum Disorders ◽  
Transcription Complexes

The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.

scholarly journals The Role of the FOXP Family of Transcription Factors in ASD

2012 ◽  
Vol 33 (5) ◽  
pp. 251-260 ◽  
Author(s):  
J. Michael Bowers ◽  
Genevieve Konopka
Keyword(s):  
Transcription Factors ◽  
Animal Behavior ◽  
Autism Spectrum ◽  
Evolution Of Language ◽  
Complex Genetics ◽  
Neurodevelopmental Disease ◽  
Key Players ◽  
The Central Nervous System ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) is a neurodevelopmental disease with complex genetics; however, the genes that are responsible for this disease still remain mostly unknown. Here, we focus on the FOXP family of transcription factors as there is emerging evidence strongly linking these genes to ASD and other genes implicated in ASD. The FOXP family of genes includes three genes expressed in the central nervous system: FOXP1, FOPX2, and FOXP4. This unique group of transcription factors has known functions in brain development as well as the evolution of language. We will also discuss the other genes including transcriptional targets of FOXP genes that have been found to be associated with language and may be important in the pathophysiology of ASD. Finally, we will review the emerging animal models currently being used to study the function of the FOXP genes within the context of ASD symptomology. The combination of gene expression and animal behavior is critical for elucidating how genes such as the FOXP family members are key players within the framework of the developing brain.

scholarly journals Association of Aryl Hydrocarbon Receptor-Related Gene Variants with the Severity of Autism Spectrum Disorders

2016 ◽  
Vol 7 ◽  
Author(s):  
Takashi X. Fujisawa ◽  
Shota Nishitani ◽  
Ryoichiro Iwanaga ◽  
Junko Matsuzaki ◽  
Chisato Kawasaki ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Aryl Hydrocarbon Receptor ◽  
Autism Spectrum ◽  
Gene Variants ◽  
Related Gene ◽  
Aryl Hydrocarbon ◽  
Spectrum Disorders

scholarly journals The murine Sim-2 gene product inhibits transcription by active repression and functional interference.

1997 ◽  
Vol 17 (9) ◽  
pp. 4933-4947 ◽  
Author(s):  
P Moffett ◽  
M Reece ◽  
J Pelletier
Keyword(s):  
Gene Product ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Regulatory Protein ◽  
Hypoxia Inducible Factor ◽  
Structure Mapping ◽  
Helix Loop Helix ◽  
Aryl Hydrocarbon ◽  
Transcription Complexes

The Drosophila single-minded (Dsim) gene encodes a master regulatory protein involved in cell fate determination during midline development. This protein is a member of a rapidly expanding family of gene products possessing basic helix-loop-helix (bHLH) and hydrophobic PAS (designated a conserved region among PER, ARNT [aryl hydrocarbon receptor nuclear translocator] and SIM) protein association domains. Members of this family function as central transcriptional regulators in cellular differentiation and in the response to environmental stimuli such as xenobiotics and hypoxia. We have previously identified a murine member of this family, called mSim-2, showing sequence homology to the bHLH and PAS domains of Dsim. Immunoprecipitation experiments with recombinant proteins indicate that mSIM-2 associates with the arnt gene product. In the present work, by using fine-structure mapping we found that the HLH and PAS motifs of both proteins are required for optimal association. Forced expression of GAL4/mSIM-2 fusion constructs in mammalian cells demonstrated the presence of two separable repression domains within the carboxy terminus of mSIM-2. We found that mSIM-2 is capable of repressing ARNT-mediated transcriptional activation in a mammalian two-hybrid system. This effect (i) is dependent on the ability of mSIM-2 and ARNT to heterodimerize, (ii) is dependent on the presence of the mSIM-2 carboxy-terminal repression domain, and (iii) is not specific to the ARNT activation domain. These results suggest that mSIM-2 repression activity can dominantly override the activation potential of adjacent transcription factors. We also demonstrated that mSIM-2 can functionally interfere with hypoxia-inducible factor 1alpha (HIF-1alpha)/ARNT transcription complexes, providing a second mechanism by which mSIM-2 may inhibit transcription.

scholarly journals The Aryl Hydrocarbon Receptor, a Basic Helix-Loop-Helix Transcription Factor of the PAS Gene Family, Is Required for Normal Ovarian Germ Cell Dynamics in the Mouse

Endocrinology ◽  
2000 ◽  
Vol 141 (1) ◽  
pp. 450-453 ◽  
Author(s):  
Rodolfo Robles ◽  
Yutaka Morita ◽  
Koren K. Mann ◽  
Gloria I. Perez ◽  
Shi Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factors ◽  
Germ Cell ◽  
Aryl Hydrocarbon Receptor ◽  
Germ Line ◽  
Wild Type ◽  
Cell Dynamics ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Aryl Hydrocarbon

Abstract The aryl hydrocarbon receptor (AhR), so-designated based on the ability of the protein to bind with and be activated by polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons, is part of an emerging family of ligand-activated transcriptional regulators that are distinct from the steroid-thyroid hormone receptor superfamily. Once bound by ligand, the AhR interacts with the AhR nuclear translocator (ARNT) protein to form the aryl hydrocarbon receptor complex (AHRC). Both subunits of the AHRC contain sequences corresponding to basic helix-loop-helix domains, a motif that is shared by a number of other dimeric transcription factors. Although the natural ligand(s) for the AhR remains to be elucidated, to date over fifteen genes, including enzymes, growth factors and other transcription factors, have been identified as potential targets for transcriptional regulation by the chemically-activated AHRC. In the ovary, PAH exposure is known to cause destruction of oocytes within immature follicles, implying that one function of the AhR is to mediate cell death signaling in the female germ line. To assess this possibility, we explored AhR expression patterns in the murine ovary, and then determined the impact of AhR-deficiency (gene knockout) on female germ cell dynamics. Immunohistochemical analysis of ovaries of wild-type female mice indicated that AhR protein was abundantly and exclusively expressed in oocytes and granulosa cells of follicles at all stages of development. Histomorphometric analysis of serial ovarian sections revealed a two-fold higher number of primordial follicles in Ahr-null versus wild-type females at day 4 postpartum. This phenotype likely results from a cell-intrinsic death defect in the developing germ line since AhR-deficiency attenuated the magnitude of oocyte apoptosis in fetal ovaries cultured without hormonal support for 72 h. We propose that the AhR, activated by an as yet unknown endogenous ligand(s), serves to regulate the size of the oocyte reserve endowed at birth by affecting germ cell death during female gametogenesis.

scholarly journals The Metallome as a Link Between the “Omes” in Autism Spectrum Disorders

2021 ◽  
Vol 14 ◽  
Author(s):  
Janelle E. Stanton ◽  
Sigita Malijauskaite ◽  
Kieran McGourty ◽  
Andreas M. Grabrucker
Keyword(s):  
Transcription Factors ◽  
Autism Spectrum Disorders ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
The Body ◽  
Causal Effects ◽  
Metal Transporters ◽  
Metal Composition ◽  
Inflammatory Processes ◽  
Spectrum Disorders

Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other “omes,” which may together result in an individual’s specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other “omes” are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other “omes” in the body in the context of “omics” studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.

Problem behavior in autism spectrum disorders: A paradigmatic self-organized perspective of network structures

2019 ◽  
Vol 42 ◽  
Author(s):  
Lucio Tonello ◽  
Luca Giacobbi ◽  
Alberto Pettenon ◽  
Alessandro Scuotto ◽  
Massimo Cocchi ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Problem Behaviors ◽  
Autism Spectrum ◽  
The Self ◽  
Network Structures ◽  
Self Organized ◽  
Critical Equilibrium ◽  
Self Organized Criticality ◽  
Acute Agitation ◽  
Spectrum Disorders

AbstractAutism spectrum disorder (ASD) subjects can present temporary behaviors of acute agitation and aggressiveness, named problem behaviors. They have been shown to be consistent with the self-organized criticality (SOC), a model wherein occasionally occurring “catastrophic events” are necessary in order to maintain a self-organized “critical equilibrium.” The SOC can represent the psychopathology network structures and additionally suggests that they can be considered as self-organized systems.

Disfluency Characteristics Observed in Young Children With Autism Spectrum Disorders: A Preliminary Report

2010 ◽  
Vol 20 (2) ◽  
pp. 42-50 ◽  
Author(s):  
Laura W. Plexico ◽  
Julie E. Cleary ◽  
Ashlynn McAlpine ◽  
Allison M. Plumb
Keyword(s):  
Autism Spectrum Disorders ◽  
Young Children ◽  
Children With Autism ◽  
Descriptive Study ◽  
Autism Spectrum ◽  
Typically Developing ◽  
Children With Asd ◽  
Young Children With Autism ◽  
Spectrum Disorders ◽  
Developmental Stuttering

This descriptive study evaluates the speech disfluencies of 8 verbal children between 3 and 5 years of age with autism spectrum disorders (ASD). Speech samples were collected for each child during standardized interactions. Percentage and types of disfluencies observed during speech samples are discussed. Although they did not have a clinical diagnosis of stuttering, all of the young children with ASD in this study produced disfluencies. In addition to stuttering-like disfluencies and other typical disfluencies, the children with ASD also produced atypical disfluencies, which usually are not observed in children with typically developing speech or developmental stuttering. (Yairi & Ambrose, 2005).

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