Transcriptional Regulatory Function Research Articles

Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function

BackgroundThe murine leukemia virus (MLV) has been a powerful model of pathogenesis for the discovery of genes involved in cancer. Its splice donor (SD’)-associated retroelement (SDARE) is important for infectivity and tumorigenesis, but the mechanism remains poorly characterized. Here, we show for the first time that P50 protein, which is produced from SDARE, acts as an accessory protein that transregulates transcription and induces cell transformation.ResultsBy infecting cells with MLV particles containing SDARE transcript alone (lacking genomic RNA), we show that SDARE can spread to neighbouring cells as shown by the presence of P50 in infected cells. Furthermore, a role for P50 in cell transformation was demonstrated by CCK8, TUNEL and anchorage-independent growth assays. We identified the integrase domain of P50 as being responsible for transregulation of the MLV promoter using luciferase assay and RTqPCR with P50 deleted mutants. Transcriptomic analysis furthermore revealed that the expression of hundreds of cellular RNAs involved in cancerogenesis were deregulated in the presence of P50, suggesting that P50 induces carcinogenic processes via its transcriptional regulatory function.ConclusionWe propose a novel SDARE-mediated mode of propagation of the P50 accessory protein in surrounding cells. Moreover, due to its transforming properties, P50 expression could lead to a cellular and tissue microenvironment that is conducive to cancer development.

Light-Induced TaHY5-7A and TaBBX-3B Physically Interact to Promote PURPLE PERICARP-MYB 1 Expression in Purple-Grained Wheat.

Purple-grained wheat (Triticum aestivum L.) is an important germplasm source in crop breeding. Anthocyanin biosynthesis in the pericarps of purple-grained wheat is largely light-dependent; however, the regulatory mechanisms underlying light-induced anthocyanin accumulation in the wheat pericarp remain unknown. Here we determined that anthocyanins rapidly accumulate in the pericarps of the purple-grained wheat cultivar Heixiaomai 76 (H76) at 16 days after pollination under light treatment. Using transcriptome sequencing, differential gene expression analysis, and phylogenetic analysis, we identified two key genes involved in light signaling in wheat: ELONGATED HYPOCOTYL 5-7A (TaHY5-7A) and B-BOX-3B (TaBBX-3B). TaHY5-7A and TaBBX-3B were highly expressed in purple-grained wheat pericarps. The heterologous expression of TaHY5-7A partially restored the phenotype of the Arabidopsis (Arabidopsis thaliana) hy5 mutant, resulting in increased anthocyanin accumulation and a shortened hypocotyl. The heterologous expression of TaBBX-3B in wild-type Arabidopsis had similar effects. TaHY5-7A and TaBBX-3B were nucleus-localized, consistent with a function in transcription regulation. However, TaHY5-7A, which lacks a transactivation domain, was not sufficient to activate the expression of PURPLE PERICARP-MYB 1 (TaPpm1), the key anthocyanin biosynthesis regulator in purple pericarps of wheat. TaHY5-7A physically interacted with TaBBX-3B in yeast two-hybrid and bimolecular fluorescence complementation assays. Additionally, TaHY5-7A, together with TaBBX-3B, greatly enhanced the promoter activity of TaPpm1 in a dual luciferase assay. Overall, our results suggest that TaHY5-7A and TaBBX-3B collaboratively activate TaPpm1 expression to promote light-induced anthocyanin biosynthesis in purple-pericarp wheat.

SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis.

Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity's impact in ALS is poorly understood. Herein, we investigated the impact of deleting the neuronal activity-stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9+ MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth, as revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF-depleted MNs was accompanied by a mild elevation of neuroinflammation and neuromuscular synapse degeneration, whereas overall MN numbers and mortality were unaffected. In SRF-deficient mice, MNs showed impaired induction of autophagy-encoding genes, suggesting a potentially new SRF function in transcriptional regulation of autophagy. Complementary, constitutively active SRF-VP16 enhanced autophagy-encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as having important TF-mediating activity-dependent effects, which might be beneficial to reduce ALS disease burden. Thus, our data identify SRF as a gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.

Transcriptome and methylome sequencing reveals altered long non-coding RNA genes expression and their aberrant DNA methylation in equine sarcoids

Recent publications confirmed that long non-coding RNAs (lncRNAs) perform an essential function in gene-specific transcription regulation. Nevertheless, despite its important role, lncRNA has not yet been described in equine sarcoids, the skin neoplasia of horses. Therefore, the aim of this study is to deepen the knowledge about lncRNA expression in the pathogenesis of equine sarcoids and provide new insight into the regulatory function of lncRNA in the bovine papillomavirus–dependent neoplasia of horse dermal tissues. RNA sequencing (RNA-seq) data from 12 equine sarcoid samples and the corresponding controls were reanalyzed in this study. A total of 3396 differentially expressed (DE) lncRNAs and 128 DElncRNA-DE genes (DEGs) pairs were identified. Differentially expressed lncRNAs predicted target genes were enriched in pathways associated with inter alia the extracellular matrix disassembly and cancer pathways. Furthermore, methylation data from the same samples were integrated into the analysis, and 12 DElncRNAs were described as potentially disturbed by aberrant methylation. In conclusion, this study presents novel data about lncRNA’s role in the pathogenesis of equine sarcoids.

Mechanism of BLIMP1/TRIM66/COX2 in human decidua participates in parturition†.

The mechanism underlying the initiation of parturition remains unclear. Cyclooxygenase 2 and prostaglandins in decidual membrane tissue play an important role in the "parturition cascade." With the advancement of gestation, the expression of the transcriptional suppressor B lymphocyte-induced maturation protein 1 in the decidual membrane gradually decreases. Through chromatin immunoprecipitation sequencing, we found that B lymphocyte-induced maturation protein 1 has a binding site in the distal intergenic of PTGS2(COX2). Tripartite motif-containing protein 66 is a chromatin-binding protein that usually performs transcriptional regulatory functions by "reading" histone modification sites in chromatin. In this study, tripartite motif-containing protein 66 exhibits the same trend of expression as B lymphocyte-induced maturation protein 1 in the decidua during gestation. Moreover, the co-immunoprecipitation assay revealed that tripartite motif-containing protein 66 combined with B lymphocyte-induced maturation protein 1. This finding indicated that tripartite motif-containing protein 66 formed a transcription complex with B lymphocyte-induced maturation protein 1, which coregulated the expression of COX2. In animal experiments, we injected si-Blimp1 adenoviruses (si-Blimp1), Blimp1 overexpression plasmid (Blimp1-OE), and Trim66 overexpression plasmid (Trim66-OE) through the tail vein of mice. The results showed that B lymphocyte-induced maturation protein 1 and tripartite motif-containing protein 66 affected the initiation of parturition in mice. Therefore, the present evidence suggests that B lymphocyte-induced maturation protein 1 and tripartite motif-containing protein 66 partially participate in the initiation of labor, which may provide a new perspective for exploring the mechanism of term labor.

Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation

The BET family protein BRD4, which forms the CDK9-containing BRD4-PTEFb complex, is considered to be a master regulator of RNA polymerase II (Pol II) pause release. Because its tandem bromodomains interact with acetylated histone lysine residues, it has long been thought that BRD4 requires these bromodomains for its recruitment to chromatin and transcriptional regulatory function. Here, using rapid depletion and genetic complementation with domain deletion mutants, we demonstrate that BRD4 bromodomains are dispensable for Pol II pause release. A minimal, bromodomain-less C-terminal BRD4 fragment containing the PTEFb-interacting C-terminal motif (CTM) is instead both necessary and sufficient to mediate Pol II pause release in the absence of full-length BRD4. Although BRD4-PTEFb can associate with chromatin through acetyl recognition, our results indicate that a distinct, active BRD4-PTEFb population functions to regulate transcription independently of bromodomain-mediated chromatin association. These findings may enable more effective pharmaceutical modulation of BRD4-PTEFb activity.

CONSTANS interacts with and antagonizes ABF transcription factors during salt stress under long-day conditions.

CONSTANS (CO) is a critical regulator of flowering that combines photoperiodic and circadian signals in Arabidopsis (Arabidopsis thaliana). CO is expressed in multiple tissues, including seedling roots and young leaves. However, the roles and underlying mechanisms of CO in modulating physiological processes outside of flowering remain obscure. Here, we show that the expression of CO responds to salinity treatment. CO negatively mediated salinity tolerance under long-day (LD) conditions. Seedlings from co-mutants were more tolerant to salinity stress, whereas overexpression of CO resulted in plants with reduced tolerance to salinity stress. Further genetic analyses revealed the negative involvement of GIGANTEA (GI) in salinity tolerance requires a functional CO. Mechanistic analysis demonstrated that CO physically interacts with 4 critical basic leucine zipper (bZIP) transcription factors; ABSCISIC ACID-RESPONSIVE ELEMENT BINDING FACTOR1 (ABF1), ABF2, ABF3, and ABF4. Disrupting these ABFs made plants hypersensitive to salinity stress, demonstrating that ABFs enhance salinity tolerance. Moreover, ABF mutations largely rescued the salinity-tolerant phenotype of co-mutants. CO suppresses the expression of several salinity-responsive genes and influences the transcriptional regulation function of ABF3. Collectively, our results show that the LD-induced CO works antagonistically with ABFs to modulate salinity responses, thus revealing how CO negatively regulates plant adaptation to salinity stress.

DJ-1 promotes cell migration by interacting with Mena, the mammalian homolog of Drosophila enabled.

DJ-1 has gained extensive attention after being identified in 2003 as a protein implicated in the pathogenesis of early-onset Parkinson's disease. Since then, efforts have revealed versatile DJ-1 functions in reactive oxygen species (ROS) control, transcriptional regulation, chaperone function, fertility, and cell transformation. Herein, we report a novel function of DJ-1 in actin cytoskeletal rearrangements. DJ-1 was identified as a new binding partner of Mena, a protein of the Enah/VASP family, and it promoted cancer cell migration by Mena-dependent actin polymerization and filopodia formation. These results suggest a novel molecular mechanism for DJ-1-dependent cancer cell invasion and metastasis.

Biosynthesis and the Transcriptional Regulation of Terpenoids in Tea Plants (Camellia sinensis).

Terpenes, especially volatile terpenes, are important components of tea aroma due to their unique scents. They are also widely used in the cosmetic and medical industries. In addition, terpene emission can be induced by herbivory, wounding, light, low temperature, and other stress conditions, leading to plant defense responses and plant-plant interactions. The transcriptional levels of important core genes (including HMGR, DXS, and TPS) involved in terpenoid biosynthesis are up- or downregulated by the MYB, MYC, NAC, ERF, WRKY, and bHLH transcription factors. These regulators can bind to corresponding cis-elements in the promoter regions of the corresponding genes, and some of them interact with other transcription factors to form a complex. Recently, several key terpene synthesis genes and important transcription factors involved in terpene biosynthesis have been isolated and functionally identified from tea plants. In this work, we focus on the research progress on the transcriptional regulation of terpenes in tea plants (Camellia sinensis) and thoroughly detail the biosynthesis of terpene compounds, the terpene biosynthesis-related genes, the transcription factors involved in terpene biosynthesis, and their importance. Furthermore, we review the potential strategies used in studying the specific transcriptional regulation functions of candidate transcription factors that have been discriminated to date.

EccDB: a comprehensive repository for eccDNA-mediated chromatin contacts in multi-species.

We developed the eccDB database to integrate available resources for extrachromosomal circular DNA (eccDNA) data. eccDB is a comprehensive repository for storing, browsing, searching, and analyzing eccDNAs from multispecies. The database provides regulatory and epigenetic information on eccDNAs, with a focus on analyzing intrachromosomal and interchromosomal interactions to predict their transcriptional regulatory functions. Moreover, eccDB identifies eccDNAs from unknown DNA sequences and analyzes the functional and evolutionary relationships of eccDNAs among different species. Overall, eccDB offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher the molecular regulatory mechanisms of eccDNAs. eccDB is freely available at http://www.xiejjlab.bio/eccDB.

LONG HYPOCOTYL IN FAR-RED 1 mediates a trade-off between growth and defense under shade in Arabidopsis.

Plants respond to vegetative shade with developmental and physiological changes that is collectively known as shade avoidance syndrome (SAS). Although LONG HYPOCOTYL IN FAR-RED 1 (HFR1) is known to be a negative regulator of SAS by forming heterodimers with other basic helix-loop-helix (bHLH) transcription factors to inhibit them, its function in genome-wide transcriptional regulation is not fully elucidated. Here, we performed RNA-sequencing analyses of hfr1-5 and HFR1 overexpression line (HFR1(ΔN)-OE) to comprehensively identify HFR1-regulated genes at different time points of shade treatment. We found that HFR1 mediates the trade-off between shade-induced growth and shade-repressed defense, by regulating the expression of relevant genes in shade. Genes involved in promoting growth, such as for auxin biosynthesis, transport, signaling and response were induced by shade but suppressed by HFR1 at both short and long durations of shade. Likewise, most ethylene-related genes were shade-induced and HFR1-repressed. On the other hand, shade suppressed defense-related genes while HFR1 induced their expression, especially under long duration of shade treatment. We demonstrated that HFR1 confers increased resistance to bacterial infection under shade.

Resequencing of durian genomes reveals large genetic variations among different cultivars.

Durian (Durio zibethinus), which yields the fruit known as the "King of Fruits," is an important economic crop in Southeast Asia. Several durian cultivars have been developed in this region. In this study, we resequenced the genomes of three popular durian cultivars in Thailand, including Kradumthong (KD), Monthong (MT), and Puangmanee (PM) to investigate genetic diversities of cultivated durians. KD, MT, and PM genome assemblies were 832.7, 762.6, and 821.6 Mb, and their annotations covered 95.7, 92.4, and 92.7% of the embryophyta core proteins, respectively. We constructed the draft durian pangenome and analyzed comparative genomes with related species in Malvales. Long terminal repeat (LTR) sequences and protein families in durian genomes had slower evolution rates than that in cotton genomes. However, protein families with transcriptional regulation function and protein phosphorylation function involved in abiotic and biotic stress responses appeared to evolve faster in durians. The analyses of phylogenetic relationships, copy number variations (CNVs), and presence/absence variations (PAVs) suggested that the genome evolution of Thai durians was different from that of the Malaysian durian, Musang King (MK). Among the three newly sequenced genomes, the PAV and CNV profiles of disease resistance genes and the expressions of methylesterase inhibitor domain containing genes involved in flowering and fruit maturation in MT were different from those in KD and PM. These genome assemblies and their analyses provide valuable resources to gain a better understanding of the genetic diversity of cultivated durians, which may be useful for the future development of new durian cultivars.

Live cell single molecule imaging reveals concentration dependent changes to dynamic behavior of nuclear receptors RAR and RXR.

Type 2 Nuclear Receptors (T2NRs) like Retinoic Acid Receptor (RAR) are believed to require heterodimerization with a common factor, the Retinoid X Receptor (RXR), to bind chromatin and regulate its target genes. Here, we deploy stroboscopic photo-activation SPT (spaSPT) to understand the molecular dynamics of the RAR/RXR system and infer different diffusion states acquired by RAR and RXR in the nucleoplasm. These states occupied by RAR and RXR presumably exist in dynamic equilibrium. Next, we ask in a complex heterodimer driven transcriptional regulatory system such as this, how is the dynamic equilibrium shifted when either of the heterodimeric partner is in excess. We find that in live cells, increasing the number of RAR molecules and not RXR molecules leads to altered chromatin binding of RAR. While increasing the number of molecules of RAR and RXR both alter the chromatin binding of RXR. Since pharmacological modulation of the RAR/RXR system is an important avenue for cancer treatments, this study constitutes a step toward understanding how perturbations of this system affect chromatin binding and possibly downstream transcriptional regulatory function.

Origin and Evolution of Marsupial-specific Imprinting Clusters Through Lineage-specific Gene Duplications and Acquisition of Promoter Differential Methylation.

Genomic imprinting is a parent-of-origin-specific expression phenomenon that plays fundamental roles in many biological processes. In animals, imprinting is only observed in therian mammals, with ∼200 imprinted genes known in humans and mice. The imprinting pattern in marsupials has been minimally investigated by examining orthologs to known eutherian imprinted genes. To identify marsupial-specific imprinting in an unbiased way, we performed RNA-seq studies on samples of fetal brain and placenta from the reciprocal cross progeny of two laboratory opossum stocks. We inferred allele-specific expression for >3,000 expressed genes and discovered/validated 13 imprinted genes, including three previously known imprinted genes, Igf2r, Peg10, and H19. We estimate that marsupials imprint ∼60 autosomal genes, which is a much smaller set compared with eutherians. Among the nine novel imprinted genes, three noncoding RNAs have no known homologs in eutherian mammals, while the remaining genes have important functions in pluripotency, transcription regulation, nucleolar homeostasis, and neural differentiation. Methylation analyses at promoter CpG islands revealed differentially methylated regions in five of these marsupial-specific imprinted genes, suggesting that differential methylation is a common mechanism in the epigenetic regulation of marsupial imprinting. Clustering and co-regulation were observed at marsupial imprinting loci Pou5f3-Npdc1 and Nkrfl-Ipncr2, but eutherian-type multi-gene imprinting clusters were not detected. Also differing from eutherian mammals, the brain and placenta imprinting profiles are remarkably similar in opossums, presumably due to the shared origin of these organs from the trophectoderm. Our results contribute to a fuller understanding of the origin, evolution, and mechanisms of genomic imprinting in therian mammals.

Development and Validation of a Bioanalytical Method for the Quantification of Nitrated Fatty Acids in Plasma Using LC-MS/MS: Application to Cardiovascular Patients

Nitrated fatty acids (NO2-FAs) are a newly discovered class of biologically active compounds with distinct biochemical features that induce physiologically beneficial alterations in transcriptional regulatory protein function, leading to a variety of modulatory and protective actions. The most common NO2-FAs identified in vivo so far are nitro oleic acid (NO2-OA), nitro linoleic acid (NO2-LA) and its structural isomer nitro-conjugated linoleic acid (NO2-cLA). Analytical limitations that compromise accurate quantitation of these endogenous compounds are their low concentrations, compromised stability and different distribution profiles in tissues and biofluids. As a result, reliable analytical methods for the quantitative determination of their endogenous levels are rare. Only NO2-OA was quantified by GC-MS while LC-MS methods are still scarce. In this work, an LC-MS/MS bioanalytical method was developed and validated for the quantification of NO2-OA and NO2-LA in human plasma via a standard addition protocol after protein precipitation, liquid extraction and LC-MS/MS analysis in the negative ion mode. Quantification was performed via multiple reaction monitoring of the transitions m/z 326 > 46 and m/z 324 > 46 for NO2-OA and NO2-LA, respectively, and m/z 269 > 250 for the internal standard heptadecanoic acid. Linear responses were observed for both analytes over the studied range (R2 = 0.9805 and 0.9644 for NO2-OA and NO2-LA, respectively). Sufficient accuracy and precision were also achieved at low, medium and high levels within the linearity range. The limits of quantification of our method (2 nM for both NO2-FAs) were below basal endogenous levels, thereby providing a good tool to accurately measure these NO2-FAs in plasma. We applied the validated method to compare NO2-OA and NO2-LA levels in the plasma of 28 ischemic heart disease (IHD) patients and 18 healthy controls. The levels of NO2-OA were found to be significantly higher in the plasma of patients (21.7 ± 9.8 nM) versus healthy controls (12.6 ± 6 nM) (p-value < 0.01). Whereas the levels of NO2-LA were comparable in both groups (3 ± 1 nM in patients, 3.2 ± 1.7 nM in controls, p-value = 0.87288). The early elevation of NO2-OA in plasma samples, which were collected 2–3 h post myocardial injury, implies the potential use of NO2-OA levels as a biomarker for IHD after further investigation with a larger number of IHD patients. To our knowledge, this is the first comparative study on the levels of NO2-FAs in humans with and without IHD.

SCREENING OF POTENTIAL CORE GENES IN PERIPHERAL BLOOD OF ADULT PATIENTS WITH SEPSIS BASED ON TRANSCRIPTION REGULATION FUNCTION.

Objective: The aim of the study is to screen transcription factor genes related to the prognosis of adult patients with sepsis. Methods: Twenty-three patients with sepsis and 10 healthy individuals admitted for RNA-seq. Differential factors were enriched by four transcription factor databases, and survival analysis was adopted for core factors. Then, target genes were submitted to STRING to constitute the protein-protein interaction network. Single-cell technology was used to localize cell lines. Finally, a transcription-target gene regulation network was constituted. Results: A total of 4,224 differentially expressed genes were obtained between sepsis and normal control groups. Protein-protein interaction results showed that FOXO3, NFKB1, SPI1, STAT5A, and PPARA were located in the center of the network. Target genes were related to cytokine-mediated signaling pathway and transcription regulator activity, etc. SPI1 was mainly located in monocyte cell lines, while FOXO3, PPARA, SP1, STAT3, and USF1 were expressed in monocyte cell lines, NK-T cell lines, and B cell lines. Compared with those in the control group, FOXO3, SP1, SPI1, STAT3, and USF1 were highly expressed in the sepsis group, while PPARA had low expression. Conclusions: Transcription factors, such as FOXO3, PPARA, SP1, SPI1, STAT3, and USF1, are correlated with the prognosis of sepsis patients and thus may have a potential research value. Clinical Trial Registration: The clinical trial registration number is ChiCTR1900021261.

The role of SWI/SNF chromatin remodelers in the repair of DNA double strand breaks and cancer therapy.

Switch/Sucrose non-fermenting (SWI/SNF) chromatin remodelers hydrolyze ATP to push and slide nucleosomes along the DNA thus modulating access to various genomic loci. These complexes are the most frequently mutated epigenetic regulators in human cancers. SWI/SNF complexes are well known for their function in transcription regulation, but more recent work has uncovered a role for these complexes in the repair of DNA double strand breaks (DSBs). As radiotherapy and most chemotherapeutic agents kill cancer cells by inducing double strand breaks, by identifying a role for these complexes in double strand break repair we are also identifying a DNA repair vulnerability that can be exploited therapeutically in the treatment of SWI/SNF-mutated cancers. In this review we summarize work describing the function of various SWI/SNF subunits in the repair of double strand breaks with a focus on homologous recombination repair and discuss the implication for the treatment of cancers with SWI/SNF mutations.

Nuclear access of DNlg3 c-terminal fragment and its function in regulating innate immune response genes

Neuroligins (NLGNs) are one of the autism susceptibility genes, however, the mechanism that how dysfunction of NLGNs leads to Autism remains unclear. More and more studies have shown that the transcriptome alteration may be one of the important factors to generate Autism. Therefore, we are very concerned about whether Neuroligins would affect transcriptional regulation, which may at last lead to Autism. As a single-transmembrane receptor, proteolytic cleavage is one of the most important posttranslational modifications of NLGN proteins. In this study, we demonstrated the existence of DNlg3 C-terminal fragment. Studies in the S2 cells and HEK293T cells showed the evidence for nuclear access of the DNlg3 C-terminal fragment. Then we identified the possible targets of DNlg3 C-terminal fragment after its nuclear access by RNA-seq. The bioinformatics analysis indicated the transcriptome alteration between dnlg3 null flies and wild type flies focused on genes for the innate immune responses. These results were consistent with the infection hypotheses for autism. Our study revealed the nuclear access ability of DNlg3 c-terminal fragment and its possible function in transcriptional regulation of the innate immune response genes. This work provides the new links between synaptic adhesion molecule NLGNs and immune activation, which may help us to get a deeper understanding on the relationship between NLGNs and Autism.

Novel de novo ZNF148 truncating variant causing autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability.

ZNF148 gene is a Krüppel-type transcription factor that has transcriptional regulatory function. Heterozygous variant in ZNF148 gene causes an intellectual disability syndrome characterized by global developmental delay, absence, or hypoplasia of corpus callosum, wide intracerebral ventricles, and dysmorphic facial features, while its associations with ASD and ADHD have not been reported. We report a new patient with intellectual disability, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). The patient had a novel heterozygous truncating variant c.1818dupC (p.Lys607Glnfs*11) in the ZNF148 gene. This variation produces a ZNF148 truncated protein with a deletion of the C-terminal activation domain and may destabilize the protein by affecting the transcriptional activation function. Brain MRI shows normal brain development. Here, we identify a novel ZNF148 heterozygous truncating variant in a patient with distinct phenotypes of ASD and ADHD, which expands the genotype-phenotype spectrum of ZNF148, and indicates ZNF148 is also a potential target gene for ASD.

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.