Function Of Transcription Factors Research Articles

Transcription Factor RhCUC3 Regulates Petal Numbers in Rose Flowers

Rose is one of the most popular ornamental plants worldwide. The double-flower trait, referring to flowers with extra petals, has been a key focus in rose breeding history. However, the genetic mechanisms regulating petal number in roses are still not fully understood. Here, we identified the CUP-SHAPED COTYLEDON 3 (RhCUC3) gene in the miniature rose (Rosa hybrida ‘Eclair’). The expression of RhCUC3 was high during the petal and stamen primordium differentiation stages but declined sharply during pistil primordium development. RhCUC3 belongs to the NAM/CUC3 subgroup of NAC transcription factors and is localized in the nucleus. The transcript level of RhCUC3 increased significantly with ABA and GA treatments and was inversely down-regulated with MeJA and 6-BA treatments. Silencing RhCUC3 using virus-induced gene silencing (VIGS) in rose ‘Eclair’ significantly decreased the number of petaloid stamens and normal petals while slightly increasing the number of stamens. Additionally, the expression of RhAG and RhAGL, two MADS-box genes associated with floral organ identity, was significantly higher in TRV-RhCUC3 compared to the TRV control. These findings suggest that RhCUC3 enhances stamen petaloidy and petal number, potentially by modulating the expression of RhAG and RhAGL, providing new insights into the function of NAC transcription factors in plants.

PbMADS49 Regulates Lignification During Stone Cell Development in 'Dangshansuli' (Pyrus bretschneideri) Fruit.

Lignified stone cell content is one of the critical factors affecting 'Dangshansuli' fruit quality. The function of MADS-box transcription factors in regulating lignin biosynthesis in pear fruit is still less. In this study, PbMADS49 gene silencing inhibited the lignin biosynthesis and stone cell secondary wall development of pear fruit mainly through reducing the expression levels of lignin monomer polymerisation key enzymes (PbPRX33 and PbPRX45). PbMADS49 was a transcriptional repressor inhibiting its transcription by binding to the CArG element in the target gene promoter. Combined with the co-expression network and promoter cis-acting element analysis, we hypothesised that PbMADS49 positively regulates the transcription of PbPRX33 through PbWRKY63. The gene silencing effect of homologous genes PbPRX33-1 and PbPRX33-2 was consistent with PbMADS49, and PbPRX33-2 was more significant than PbPRX33-1. This study shows that PbMADS49 is a positive regulator of stone cell lignification, providing new insights into the development mechanism of pear stone cells.

The SEPALLATA-like gene HrSEP1 in Hippophae rhamnoides regulates flower development by interacting with other MADS-box subfamily genes

MADS-box genes are classified into five categories: ABCDE, including SEP1, SEP2, SEP3, SEP4, and other homologous genes, which play important roles in floral organ development. In this study, the cDNA sequence of the HrSEP1 gene was cloned by RT-PCR and confirmed that this gene belongs to the MADS-box gene family. In addition, subcellular localization experiments showed that the HrSEP1 protein was localized in the nucleus. We verified the interaction of HrSEP1 with HrSOC1, HrSVP, and HrAP1 using yeast two-hybrid and bimolecular fluorescence complementation assays. These genes jointly regulate the growth and development of floral organs. We also found a strong synergy between HrSEP1 and AP1 genes in sepals, petals, and stamens by transgenic methods and fluorescence quantitative PCR, suggesting that HrSEP1 and AP1 may co-regulate the development of these structures. In conclusion, the expression of HrSEP1 has a certain effect on the development of floral organs, and these findings lay the foundation for further research on the biological functions of MADS transcription factors in Hippophae rhamnoides.

Genome-wide identification of 1R-MYB transcription factors family and functional characterization of TrMYB130 under drought stresses in Trifolium repens (L.).

White clover (Trifolium repens L.) is a high-quality leguminous forage, but its short rooting habit, poor transpiration tolerance, and drought tolerance, have become a key factor restricting its growth and cultivation. 1R-MYB transcription factors (TFs) are a significant subfamily of TFs in plants, playing a vital role in regulating plant responses to drought stress, however, knowledge about the role of 1R-MYB transcription factors in white clover is still limited. We identified 134 1R-MYB members, which were unevenly designated onto 16 chromosomes and divided phylogenetically into five subgroups. The members of the same subgroup had conserved motifs. Collinearity analysis revealed that segmental and tandem duplications significantly contributed to the expansion of the Tr1R-MYBs. Tr1R-MYBs promoter region enriched with potential drought cis-acting regulatory elements. The RT-qPCR results show that the five Tr1R-MYB genes (TrMYB41, TrMYB49, TrMYB94, TrMYB125, TrMYB130) have a certain degree of response under drought stress conditions but exhibited different expression profiles. Furthermore, subcellular localization analysis showed that the TrMYB130 protein is primarily located in the nucleus. Overexpression of this protein in transgenic Arabidopsis (Arabidopsis thaliana L.) was found to impair drought tolerance. Our findings will establish a basis for deeper investigation into the characteristics and functions of 1R-MYB TFs, as well as for employing genetic engineering techniques to improve white clover.

Identification of R2R3-MYB Transcription Factor Family Based on Amaranthus tricolor Genome and AtrMYB72 Promoting Betalain Biosynthesis by Directly Activating AtrCYP76AD1 Expression

MYB (myeloblastosis) is one of the most abundant transcription factors in plants which regulates various biological processes. The molecular characteristics and function of R2R3-MYB transcription factors in amaranth remain unclear. In this study, 73 R2R3-MYB members were identified from the amaranth genome database and we further analyzed their chromosome position, conserved motifs, physiological and biochemical features, collinearity relationships, gene structure, phylogeny and cis-acting element. Based on the phylogenetic and expression pattern analysis, 14 candidate R2R3-MYB genes might be involved in the betalain synthesis. Amongst the 14 candidate R2R3-MYB genes, the expression level of AtrMYB72 was higher in ‘Suxian No.1’ than ‘Suxian No.2’, and also higher in the red section than in the green section of the same leaf in Amaranthus. The overexpression vector pCambia1301-AtrMYB72-GUS and VIGS (virus-induced gene silencing) vector pTRV2- AtrMYB72 were transferred into leaves of ‘Suxian No.1’ via an Agrobacterium-mediated method. The results showed that AtrMYB72 overexpression could promote betalain synthesis. A yeast one-hybrid assay and dual luciferase reporter gene assay demonstrated that AtrMYB72 could bind to the AtrCYP76AD1 promoter to promote betalain synthesis. These results indicated that AtrMYB72 promoted betalain biosynthesis in amaranth by activating the AtrCYP76AD1 transcription. Our results could provide new insights into the betalain biosynthesis in amaranth.

PbMYB5 transcription factor plays a role in regulating anthocyanin biosynthesis in pear (Pyrus bretschneideri Rehd) skin.

The phenylacetone pathway, which encompasses flavonoids, lignin, and other compounds, is of paramount importance in determining the quality of pear fruit. Nevertheless, the precise regulatory functions of R2R3-MYB transcription factors in the metabolic pathways that regulate pear color changes remain unclear. In this study, we isolated an R2R3-PbMYB5(PbMYB5) transcription factor from 'Red Zaosu' pears and demonstrated that it influenced the expression of several genes, including PbCAD1, PbF5H, PbLAR, PbANR, and PbUFGT. The overexpression of PbMYB5 resulted in a notable elevation in anthocyanin concentration within the pear epidermis. Further research has shown that PbMYB5 is able to bind to PbANS and also has interactions with PbbHLH3 and PbbHLH33.We proposed that PbMYB5 forms a complex with PbbHLH3, PbbHLH33, and PbWD40 to activate PbANS and promote anthocyanin accumulation. This study offers new insights into the regulation of various metabolic pathways that impact fruit coloration.

The OsGATA gene family as a promising candidate for applying the CRISPR/Cas genome editing technology to improve the nutritional and yield qualities of rice (Oryza sativa L.)

Molecular breeding of rice (Oryza sativa L.) for yield is of great importance for ensuring food security of the population. Living organisms manifest genetically determined responses to environmental factors, including stressors. Photosynthetic activity affects all metabolic processes in plant cells. The genes involved in photosynthesis, in their turn, are regulated by differentially expressed genes associated with circadian rhythms. Plants, as sedentary organisms, require more efficient regulation of gene expression. GATA factors are transcription factors (TFs) that affect the production of phytohormones and mediate the stress response. GATA factors are divided into four main classes (A to D), based on the difference in the structure of the zinc finger domain, and into seven subfamilies, depending on the availability of additional domains. GATA TFs incorporate domain structures that may be involved in the regulation of circadian rhythms. Effects on the circadian rhythms influence other regulatory metabolic pathways in plants, which makes the study of genes associated with circadian rhythms relevant and significant. The most well-known and popular method of gene editing at the moment is the CRISPR/Cas technology. More than 30 rice genes were successfully genomically edited using the CRISPR/Cas technology in the period from 2018 through 2023. This helped to improve their valuable agronomic traits.This review summarizes all information about the classification and known functions of OsGATA genes and OsGATA TFs and provides evidence for the possibility of influencing the regulation of rice photoperiodicity by editing these genes.

A cutting-edge investigation of the multifaceted role of SOX family genes in cancer pathogenesis through the modulation of various signaling pathways.

This detailed study examines the complex role of the SOX family in various tumorigenic contexts, offering insights into how these transcription factors function in cancer. As the study progresses, it explores the specific contributions of each SOX family member. The significant roles of the SOX family in the oncogenic environment are well-recognized, highlighting a range of regulatory mechanisms that influence tumor progression. In brain, lung, and colorectal cancers, SOX types like SOX2, SOX3, and SOX4 promote the migration, proliferation, and angiogenesis of cancer cells. Conversely, in pancreatic, gastric, and breast cancers, SOX types, including SOX1, SOX9, and SOX17 inhibit various cancer cell activities such as proliferation and invasion. This thorough investigation enhances our understanding of the SOX family's complex role in cancer, establishing a foundation for future research and potential therapeutic strategies targeting these versatile transcription factors.

Deubiquitinase MYSM1 drives myocardial ischemia/reperfusion injury by stabilizing STAT1 in cardiomyocytes.

Rationale: Myocardial ischemia/reperfusion (I/R) injury leads to irreversible cardiomyocyte death and aggravates myocardial infarction. Deubiquitinating enzymes (DUBs) are essential for maintaining substrate protein stability and functionality, playing significant roles in cardiac pathophysiology. In this study, we aimed to clarify the regulatory role of a DUB, Myb-like, SWIRM, and MPN domains 1 protein (MYSM1), in myocardial I/R injury and explore the molecular mechanism behind. Methods and Results: Firstly, it was found that the expression of MYSM1 positively correlates with myocardial I/R injury. Genetic knockdown of MYSM1 significantly conferred protection against I/R injury in hearts. Correspondingly, AAV9-mediated cardiomyocyte-specific knockdown of MYSM1 had a therapeutic effect on myocardial I/R injury. Through a comprehensive proteome-wide quantitative analysis, we identified signal transducer and activator of transcription 1 (STAT1) as the direct substrate of MYSM1. Mechanistically, MYSM1 mediated the K63-linked deubiquitination and stabilization of STAT1 at position K379 via its MPN metalloprotease domain. Additionally, MYSM1 initiates the expression of necroptosis-related genes by promoting the transcription factor function of STAT1. Conclusion: This study illustrated a MYSM1-STAT1 axis in regulating myocardial I/R injury and identified MYSM1 as a pharmacological target for myocardial I/R injury.

Systematic characterization of the bZIP gene family in Colletotrichum siamense and functional analysis of three family members

The basic leucine zipper (bZIP) transcription factors (TFs) play important roles in many physiological processes of plant-pathogenic fungi, especially concerning fungal development, fungicide resistance, and pathogenicity. Colletotrichum siamense is the predominant species causing Colletotrichum leaf disease (CLD) in rubber trees. However, little is known about the bZIP genes in C. siamense. In this study, 25 bZIP genes were systematically identified in the genome of C. siamense, and molecular features were characterized. Evolutionarily, the CsbZIP genes were divided into 11 groups, with the members in the same group sharing similar gene structures and conserved protein motif organizations. Furthermore, protein-protein interaction (PPI) analysis revealed that 15 bZIP proteins had functional partners in common or interacted with other CsbZIP proteins. Additionally, the expression of 23 CsbZIP genes changed in response to the antifungal chemicals melatonin, prochloraz, and thymol, and the genes could be divided into three clusters based on their expression patterns. Finally, gene deletion mutants of CsbZIP01/09/17 were constructed and functional analysis indicated that these genes operated as important regulators of mycelial growth, fungicide resistance, ergosterol biosynthesis, and virulence in C. siamense. This study provided the foundations crucial for further investigation of the functions of CsbZIP TFs in fungicide resistance and virulence.

A novel transcription factor OsMYB73 affects grain size and chalkiness by regulating endosperm storage substances' accumulation-mediated auxin biosynthesis signalling pathway in rice.

Enhanced grain yield and quality traits are everlasting breeding goals. It is therefore of great significance to uncover more genetic resources associated with these two important agronomic traits. Plant MYB family transcription factors play important regulatory roles in diverse biological processes. However, studies on genetic functions of MYB in rice yield and quality are rarely to be reported. Here, we investigated a nucleus-localized transcription factor OsMYB73 which is preferentially expressed in the early developing pericarp and endosperm. We generated targeted mutagenesis of OsMYB73 in rice, and the mutants had longer grains with obvious white-belly chalky endosperm appearance phenotype. The mutants displayed various changes in starch physicochemical characteristics and lipid components. Transcriptome sequencing analysis showed that OsMYB73 was chiefly involved in cell wall development and starch metabolism. OsMYB73 mutation affects the expression of genes related to grain size, starch and lipid biosynthesis and auxin biosynthesis. Moreover, inactivation of OsMYB73 triggers broad changes in secondary metabolites. We speculate that rice OsMYB73 and OsNF-YB1 play synergistic pivotal role in simultaneously as transcription activators to regulate grain filling and storage compounds accumulation to affect endosperm development and grain chalkiness through binding OsISA2, OsLTPL36 and OsYUC11. The study provides important germplasm resources and theoretical basis for genetic improvement of rice yield and quality. In addition, we enriches the potential biological functions of rice MYB family transcription factors.

Genome-wide phenotypic profiling of transcription factors and identification of novel targets to control the virulence of Vibrio vulnificus.

For successful infection, the life-threatening pathogen Vibrio vulnificus elaborately regulates the expression of survival and virulence genes using various transcription factors (TFs). In this study, a library of the V. vulnificus mutants carrying specific signature tags in 285 TF genes was constructed and subjected to 16 phenotypic analyses. Consequently, 89 TFs affecting more than one phenotype of V. vulnificus were identified. Of these, 59 TFs affectedthe in vitro survival including growth, stress resistance, biofilm formation and motility, and 64 TFs affected the virulence of V. vulnificus. Particularly, 27 of the 64 TFs enhanced the in vitro hemolytic or cytotoxic activities, and 8 of the 27 TFs also increased the in vivo brine shrimp or murine infectivities of V. vulnificus. Among the eight TFs, HlyU, IscR, NagC, MetJ and Tet2 did not affect the growth of V. vulnificus but still regulated the expression of major exotoxin genes, including rtxA, vvhA and plpA, thereby emerging as potential drug targets for anti-virulence therapies with low selective pressure for developing resistance. Altogether, this study characterized the functions of TFs at a genome-wide scale and identified novel targets to control the virulence of V. vulnificus.

SlUPA-like, a bHLH Transcription Factor in Tomato (Solanum lycopersicum), Serves as the Crosstalk of GA, JA and BR.

The bHLH (basic Helix-Loop-Helix) transcription factor serves as pivotal controller in plant growth and development. In a previous study, the overexpression of SlUPA-like in Solanum lycopersicum L. Ailsa Craig (AC++) altered the JA (Jasmonic acid) response and endogenous GA (Gibberellic acid) content. However, the detailed regulation mechanism was not fully explored. In the present research, we found that the overexpression of SlUPA-like influenced the accumulation of GA, JA and BR (Brassinolide). RNA-Seq data illustrated that the expression levels of genes related to these plant hormones were significantly affected. Additionally, the interaction of SlUPA-like with SlMYB21, SlMYC2 and SlDELLA was characterized by employing Y2H (Yeast Two-Hybrid) and BiFC (Bimolecular Fluorescence Complementation) assay. Furthermore, Dual-LUC (Dual-Luciferase) assay and EMSA (Electrophoretic Mobility Shift Assay) identified that SlUPA-like directly targeted the E-box motif in the promoter of SlGID2 and activated the transcription of SlGID2. These results shed light on the potential role of SlUPA-like in mediating crosstalk among multiple plant hormones and established a robust theoretical framework for further unraveling the functions of SlUPA-like transcription factors in the context of plant growth and hormone signal transduction.

E. coli transcription factors regulate promoter activity by a universal, homeostatic mechanism.

Transcription factors (TFs) may activate or repress gene expression through an interplay of different mechanisms, including RNA polymerase (RNAP) recruitment, exclusion, and initiation. TFs often have drastically different regulatory behaviors depending on promoter context and interacting cofactors. However, the detailed mechanisms by which each TF affects transcription and produce promoter-dependent regulation is unclear. Here, we discover that a simple model explains the regulatory effects of E. coli TFs in a range of contexts. Specifically, we measure the relationship between basal promoter activity and its regulation by diverse TFs and find that the contextual changes in TF function are determined entirely by the basal strength of the regulated promoter: TFs exert lower fold-change on stronger promoters under a precise inverse scaling. Remarkably, this scaling relationship holds for both activators and repressors, indicating a universal mechanism of gene regulation. Our data, which spans between 100-fold activation to 1000-fold repression, is consistent with a model of regulation driven by stabilization of RNAP at the promoter for every TF. Crucially, this indicates that TFs naturally act to maintain homeostatic expression levels across genetic or environmental perturbations, ensuring robust expression of regulated genes .

Evolution and Function of MADS-Box Transcription Factors in Plants.

The MADS-box transcription factor (TF) gene family is pivotal in various aspects of plant biology, particularly in growth, development, and environmental adaptation. It comprises Type I and Type II categories, with the MIKC-type subgroups playing a crucial role in regulating genes essential for both the vegetative and reproductive stages of plant life. Notably, MADS-box proteins can influence processes such as flowering, fruit ripening, and stress tolerance. Here, we provide a comprehensive overview of the structural features, evolutionary lineage, multifaceted functions, and the role of MADS-box TFs in responding to biotic and abiotic stresses. We particularly emphasize their implications for crop enhancement, especially in light of recent advances in understanding the impact on sugarcane (Saccharum spp.), a vital tropical crop. By consolidating cutting-edge findings, we highlight potential avenues for expanding our knowledge base and enhancing the genetic traits of sugarcane through functional genomics and advanced breeding techniques. This review underscores the significance of MADS-box TFs in achieving improved yields and stress resilience in agricultural contexts, positioning them as promising targets for future research in crop science.

SE-lncRNAs in Cancer: Classification, Subcellular Localisation, Function and Corresponding TFs.

Emerging evidence highlights certain long noncoding RNAs (lncRNAs) transcribed from or interacting with super-enhancer (SE) regulatory elements. These lncRNAs, known as SE-lncRNAs, are strongly linked to cancer and regulate cancer progression through multiple interactions with downstream targets. The expression of SE-lncRNAs is controlled by various transcription factors (TFs), and dysregulation of these TFs can contribute to cancer development. In this review, we discuss the characteristics, classification and subcellular distribution of SE-lncRNAs and summarise the role of key TFs in the transcription and regulation of SE-lncRNAs. Moreover, we examine the distinct functions and potential mechanisms of SE-lncRNAs in cancer progression.

Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.

RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.

The function of the ZFP189 transcription factor in the nucleus accumbens facilitates cocaine-specific transcriptional and behavioral adaptations.

Distinguishing the brain mechanisms affected by distinct addictive drugs may inform targeted therapies against specific substance use disorders (SUDs). Here, we explore the function of a drug-associated, transcriptionally repressive transcription factor (TF), ZFP189, whose expression in the nucleus accumbens (NAc) facilitates cocaine-induced molecular and behavioral adaptations. To uncover the necessity of ZFP189-mediated transcriptional control in driving cocaine-induced behaviors, we created synthetic ZFP189 TFs of distinct transcriptional function, including ZFP189VPR, which activates the expression of target genes and exerts opposite transcriptional control to the endogenously repressive ZFP189. By virally delivering synthetic ZFP189 TFs to the NAc of mice, we discover that the transcriptional control exerted by synthetic or endogenous ZFP189 solely alters behavioral adaptations to cocaine but not morphine, saline, or sucrose. Further, these synthetic ZFP189 TFs are only capable of producing gene-expression changes in rodents exposed to cocaine, but not morphine or saline. In these cocaine exposed mice, the gene-expression profile produced by ZFP189VPR is inversely related to the cocaine-induced transcriptional response, as characterized by Upstream Regulator Analysis in Ingenuity Pathway Analysis. Lastly, we demonstrate that NAc ZFP189WT increases vulnerability to cocaine reinforcement through selective sensitization to the reinforcing effects of small cocaine doses. In contrast, ZFP189VPR treated mice do not experience changes in cocaine sensitivity and had lower rates of cocaine self-administration. Collectively, this research describes the brain mechanisms by which a TF specifically coordinates the molecular adaptations that produce increased cocaine addiction-like behaviors. The use of synthetic ZFP189VPR uncovers novel strategies for therapeutic interventions to potentially halt these cocaine-induced transcriptional processes.

Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function.

Phase separation explains the exquisite spatial and temporal regulation of many biological processes, but the role of transcription factor-mediated condensates in gene regulation is contentious, requiring head-to-head comparison of competing models. Here, we focused on the prototypical yeast transcription factor Gcn4 and assessed two models for gene transcription activation, i.e., mediated via soluble complexes or transcriptional condensates. Both models rely on the ability of transcription factors and coactivators to engage in multivalent interactions. Unexpectedly, we found that propensity to form homotypic Gcn4 condensates does not correlate well with transcriptional activity. Contrary to prevailing models, binding to DNA suppresses Gcn4 phase separation. Notably, the ability of Gcn4 to form soluble complexes with coactivator subunit Med15 closely mirrored the propensity to recruit Med15 into condensates, indicating that these properties are intertwined and cautioning against interpretation of mutational data without head-to-head comparisons. However, Gcn4 variants with the highest affinity for Med15 do not function as well as expected and instead have activities that reflect their abilities to phase separate with Med15. These variants therefore indeed form cellular condensates, and those attenuate activity. Our results show that transcription factors can function as soluble complexes as well as condensates, reconciling two seemingly opposing models, and have implications for other phase-separating systems.

Transcription factor TCF4: structure, function, and associated diseases.

Our understanding of human genes - particularly their structure, functions, and regulatory mechanisms - is still limited. The biological role of approximately 20 % of human proteins has not been established yet, and the molecular functions of the known part of the proteome remain poorly understood. This hinders progress in basic and applied biological and medical sciences, especially in treating hereditary diseases, which are caused by mutations and polymorphic variants in individual genes. Therefore, it is crucial to comprehend the mechanisms of protein functioning to address this problem. This further emphasizes the importance of investigating gene functions and molecular pathogenetic pathways associated with single-gene inherited diseases. This review focuses on the TCF4 gene that encodes a transcription factor crucial for nervous system development and functioning. Pathogenic variants in this gene have been linked to a rare genetic disorder, Pitt-Hopkins syndrome, and TCF4 polymorphic variants are associated with several socially significant diseases, including various psychiatric disorders. The pathogenetic mechanisms of these conditions remain unexplored, and the knowledge about TCF4 upregulation and its target genes is limited. TCF4 can be expressed in various isoforms due to the complex structure and regulation of its gene, which complicates the investigation of the protein's functions. Here, we consider the structure and functions of the TCF4 transcription factor. We discuss its potential target genes and the possible loss-of-function pathogenetic mechanisms identified in animal and cellular models of Pitt-Hopkins syndrome. The review also examines the advantages and limitations of potential therapies for Pitt-Hopkins syndrome that are based on TCF4 dosage compensation or altering the activity of TCF4 target genes.