A possible role for G-quadruplexes formation and DNA methylation at IMOOD gene promoter in Obsessive Compulsive Disorder
Annalaura SabatucciAntonio GirellaMartina Di BartolomeoMariangela PucciMatteo VismaraBeatrice BenattiIsobel A BlacksellDianne CooperEnrico DaineseFulvio D’AcquistoBernardo Dell’OssoClaudio D’Addario
0
Citation
48
Reference
10
Related Paper
Abstract:
Obsessive Compulsive Disorder (OCD) is a mental health condition still classified and diagnosed with subjective interview-based assessments and which molecular clues have not completely been elucidated. We have recently identified a new regulator of anxiety and OCD-like behavior called Immuno-moodulin (IMOOD) and, here, we report that IMOOD gene promoter is differentially methylated in OCD subjects when compared to genomic material collected from healthy controls and this alteration is significantly correlated with the increased expression of the gene in OCD. We also demonstrated that IMOOD promoter can form G-quadruplexes and we suggest that, in homeostatic conditions, these structures could evoke DNA-methylation silencing the gene, whereas in pathological conditions, like OCD, could induce gene expression making the promoter more accessible to transcriptional factors. We here thus further suggest IMOOD as a new biomarker for OCD and also hypothesize new mechanisms of gene regulation.Transcription is the first step in the course of decoding the structural information of proteins in the genome into functional products. Transcriptional regulation is thus a universal mode of regulatory mechanism of gene expression. Methods of studying transcriptional regulation are diverse and main procedures to measure transcriptional activity and to characterize cis- and trans-acting elements are summarized. Studies on transcriptional regulation of the genes in the airway, including those of surfactant apoproteins and of Clara cell 10 kDa protein (CC10), have revealed the presence of trans-acting elements, which are the transcription factors found in other organ such as the liver and thyroid gland, suggesting a common regulatory mechanism for cell-type specific transcription in some organs and tissues. Such studies have also provided possible means to transfer genes, in a cell-type specific manner, for therapeutic purposes.
Transcription
Cite
Citations (0)
Gene transcription is regulated with distinct sets of regulatory factors at multiple levels. Transcriptional and post-transcriptional regulation constitute two major regulation modes of gene expression to either activate or repress the initiation of transcription and thereby control the number of proteins synthesized during translation. Disruptions of the proper regulation patterns at transcriptional and post-transcriptional levels are increasingly recognized as causes of human diseases. Consequently, identifying the differential gene expression at transcriptional and post-transcriptional levels respectively is vital to identify potential disease-associated and/or causal genes and understand their roles in the disease development. Here, we proposed a novel method with a linear mixed model that can identify a set of differentially expressed genes at transcriptional and post-transcriptional levels. The simulation and real data analysis showed our method could provide an accurate way to identify genes subject to aberrant transcriptional and post-transcriptional regulation and reveal the potential causal genes that contributed to the diseases.
Post-transcriptional regulation
Transcription
YY1
Transcriptional activity
Cite
Citations (16)
Proper regulation of gene expression is required by bacterial pathogens to respond to continually changing environmental conditions and the host response during the infectious process. While transcriptional regulation is perhaps the most well understood form of controlling gene expression, recent studies have demonstrated the importance of post-transcriptional mechanisms of gene regulation that allow for more refined management of the bacterial response to host conditions. Yersinia species of bacteria are known to use various forms of post-transcriptional regulation for control of many virulence-associated genes. These include regulation by cis- and trans-acting small non-coding RNAs, RNA-binding proteins, RNases, and thermoswitches. The effects of these and other regulatory mechanisms on Yersinia physiology can be profound and have been shown to influence type III secretion, motility, biofilm formation, host cell invasion, intracellular survival and replication, and more. In this review, we will discuss these and other post-transcriptional mechanisms and their influence on virulence gene regulation, with a particular emphasis on how these processes influence the virulence of Yersinia in the host.
Yersinia
Post-transcriptional regulation
Cite
Citations (42)
Sigma factor
Post-transcriptional regulation
Cite
Citations (70)
Transcriptional regulation by transcription factors and post-transcriptional regulation by microRNAs constitute two major modes of regulation of gene expression. While gene expression motifs incorporating solely transcriptional regulation are well investigated, the dynamics of motifs with dual strategies of regulation, i.e., both transcriptional and post-transcriptional regulation, have not been studied as extensively. In this paper, we probe the dynamics of a four-gene motif with dual strategies of regulation of gene expression. Some of the functional characteristics are compared with those of a two-gene motif, the genetic toggle, employing only transcriptional regulation. Both the motifs define positive feedback loops with the potential for bistability and hysteresis. The four-gene motif, contrary to the genetic toggle, is found to exhibit bistability even in the absence of cooperativity in the regulation of gene expression. The four-gene motif further exhibits a novel dynamical feature in which two regions of monostability with linear threshold response are separated by a region of bistability with digital response. Using the linear noise approximation, we further show that the coefficient of variation (a measure of noise), associated with the protein levels in the steady state, has a lower magnitude in the case of the four-gene motif as compared to the case of the genetic toggle. We next compare transcriptional with post-transcriptional regulation from an information theoretic perspective. We focus on two gene expression motifs, Motif 1 with transcriptional regulation and Motif 2 with post-transcriptional regulation. We show that amongst the two motifs, Motif 2 has a greater capacity for information transmission for an extended range of parameter values.
Motif (music)
Cooperativity
Gene regulatory network
Cite
Citations (4)
Significance Cells regulate the activity of genes in a variety of ways. For example, they regulate transcription through DNA binding proteins called transcription factors, and they regulate mRNA stability and processing through RNA binding proteins. Based on current knowledge, transcriptional regulation is more widespread and is involved in many more evolutionary adaptations than posttranscriptional regulation. The reason could be that transcriptional regulation is studied more intensely. We suggest instead that transcriptional regulation harbors an intrinsic evolutionary advantage: when mutations change transcriptional regulation, they are more likely to bring forth novel patterns of such regulation. That is, transcriptional regulation is more evolvable. Our analysis suggests a reason why a specific kind of gene regulation is especially abundant in the living world.
Post-transcriptional regulation
Transcription
Cite
Citations (39)
myc family genes (c-, N-, and L-myc) have been shown to be differentially expressed with respect to tissue type and developmental stage. To define and compare the regulatory mechanisms governing their differential developmental expression, we examined the transcriptional regulation of each myc family member during murine postnatal brain and liver development. Nuclear run-on transcription assays demonstrated that both the rate of transcriptional initiation and the degree of transcriptional blocking contribute in a complex manner to the regulation of all three genes. During postnatal brain development, the relative contribution of each transcriptional control mechanism to the regulation of myc family gene expression was found to be different for each gene. For instance, while modulation of transcriptional attenuation did not appear to contribute to the down-regulation of L-myc expression, attenuation was found to be the dominant mechanism by which steady-state N-myc mRNA levels were down-regulated. Different transcriptional strategies were found to be employed in newborn versus adult developing liver for repression of N- and L-myc expression. Undetectable steady-state N- and L-myc mRNA levels in newborn liver were associated with a very low rate of transcriptional initiation, whereas the lack of N- and L-myc expression at the adult stage was accompanied by a high rate of initiation and a striking degree of transcriptional attenuation. Transcriptional attenuation in the N-myc gene was found to map to a region encoding a potential stem-loop structure followed by a thymine tract within the first exon and was not dependent on the use of a specific transcriptional start site.
Post-transcriptional regulation
Cite
Citations (23)
myc family genes (c-, N-, and L-myc) have been shown to be differentially expressed with respect to tissue type and developmental stage. To define and compare the regulatory mechanisms governing their differential developmental expression, we examined the transcriptional regulation of each myc family member during murine postnatal brain and liver development. Nuclear run-on transcription assays demonstrated that both the rate of transcriptional initiation and the degree of transcriptional blocking contribute in a complex manner to the regulation of all three genes. During postnatal brain development, the relative contribution of each transcriptional control mechanism to the regulation of myc family gene expression was found to be different for each gene. For instance, while modulation of transcriptional attenuation did not appear to contribute to the down-regulation of L-myc expression, attenuation was found to be the dominant mechanism by which steady-state N-myc mRNA levels were down-regulated. Different transcriptional strategies were found to be employed in newborn versus adult developing liver for repression of N- and L-myc expression. Undetectable steady-state N- and L-myc mRNA levels in newborn liver were associated with a very low rate of transcriptional initiation, whereas the lack of N- and L-myc expression at the adult stage was accompanied by a high rate of initiation and a striking degree of transcriptional attenuation. Transcriptional attenuation in the N-myc gene was found to map to a region encoding a potential stem-loop structure followed by a thymine tract within the first exon and was not dependent on the use of a specific transcriptional start site.
Post-transcriptional regulation
Cite
Citations (10)
SUMMARY The leap from simple unicellularity to complex multicellularity remains one of life's major enigmas. The origins of metazoan developmental gene regulatory mechanisms are sought by analyzing gene regulation in extant eumetazoans, sponges, and unicellular organisms. The main hypothesis of this manuscript is that, developmental enhancers evolved from unicellular inducible promoters that diversified the expression of regulatory genes during metazoan evolution. Promoters and enhancers are functionally similar; both can regulate the transcription of distal promoters and both direct local transcription. Additionally, enhancers have experimentally characterized structural features that reveal their origin from inducible promoters. The distal co‐operative regulation among promoters identified in unicellular opisthokonts possibly represents the precursor of distal regulation of promoters by enhancers. During metazoan evolution, constitutive‐type promoters of regulatory genes would have acquired novel receptivity to distal regulatory inputs from promoters of inducible genes that eventually specialized as enhancers. The novel regulatory interactions would have caused constitutively expressed genes controlling differential gene expression in unicellular organisms to become themselves differentially expressed. The consequence of the novel regulatory interactions was that regulatory pathways of unicellular organisms became interlaced and ultimately evolved into the intricate developmental gene regulatory networks (GRNs) of extant metazoans.
Multicellular organism
Gene regulatory network
Cite
Citations (30)
One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model. Given a high-dimensional transcriptional profiling dataset from human blood leukocytes, an elementary set of temporal dynamic responses which capture the essence of a pro-inflammatory phase, a counter-regulatory response and a dysregulation in leukocyte bioenergetics has been extracted. Upon identification of these expression patterns, fourteen inflammation-specific gene batteries that represent groups of hypothetically 'coregulated' genes are proposed. Subsequently, statistically significant cis-regulatory modules (CRMs) are identified and decomposed into a list of critical transcription factors (34) that are validated largely on primary literature. Finally, our analysis further allows for the construction of a dynamic representation of the temporal transcriptional regulatory program across the host, deciphering possible combinatorial interactions among factors under which they might be active. Although much remains to be explored, this study has computationally identified key transcription factors and proposed a putative time-dependent transcriptional regulatory program associated with critical transcriptional inflammatory responses. These results provide a solid foundation for future investigations to elucidate the underlying transcriptional regulatory mechanisms under the host inflammatory response. Also, the assumption that coexpressed genes that are functionally relevant are more likely to share some common transcriptional regulatory mechanism seems to be promising, making the proposed framework become essential in unravelling context-specific transcriptional regulatory interactions underlying diverse mammalian biological processes.
Cite
Citations (20)