Search Results (6)

The Krüppel-like factor (KLF) family represents a group of transcription factors (TFs) performing different biological processes that are crucial for proper neuronal function, including neuronal development, synaptic plasticity, and neuronal survival. As reported, genetic variants within the KLF family have been associated with a wide spectrum of neurodevelopmental and psychiatric symptoms. In a patient exhibiting attention deficit hyperactivity disorder (ADHD) combined with both neurodevelopmental and psychiatric symptoms, whole-exome sequencing (WES) analysis revealed a de novo heterozygous variant within the Krüppel-like factor 13 (KLF13) gene, which belongs to the KLF family and regulates axonal growth, development, and regeneration in mice. Moreover, in silico analyses pertaining to the likely pathogenic significance of the variant and the impact of the mutation on the KLF13 protein structure suggested a potential deleterious effect. In fact, the variant was localized in correspondence to the starting residue of the N-terminal domain of KLF13, essential for protein–protein interactions, DNA binding, and transcriptional activation or repression. This study aims to highlight the potential involvement of the KLF13 gene in neurodevelopmental and psychiatric disorders. Nevertheless, we cannot rule out that excluded variants, those undetectable by WES, or the polygenic risk may have contributed to the patient’s phenotype given ADHD’s high polygenic risk. However, further functional studies are required to validate its potential contribution to these disorders. Full article

Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes. Krüppel-like Factor 9 (KLF9) and Krüppel-like Factor 13 (KLF13) are two of the smallest members of the SP/KLF family, are paralogous, emerged early in metazoan evolution, and are highly conserved. Paradoxically, while most similar in primary sequence, KLF9 and KLF13 display many distinct roles in target cells. In this article, we summarize the work that has identified the roles of KLF9 (and to a lesser degree KLF13) in tumor suppression or promotion via unique effects on differentiation, pro- and anti-inflammatory pathways, oxidative stress, and tumor immune cell infiltration. We also highlight the great diversity of miRNAs, lncRNAs, and circular RNAs which provide mechanisms for the ubiquitous tumor-specific suppression of KLF9 mRNA and protein. Elucidation of KLF9 and KLF13 in cancer biology is likely to provide new inroads to the understanding of oncogenesis and its prevention and treatments. Full article

The Krüppel-like factor 13 (KLF13) has emerged as an important transcription factor involved in essential processes of the central nervous system (CNS). It predominantly functions as a transcriptional repressor, impacting the activity of several signaling pathways with essential roles in the CNS, including the JAK/STAT pathway, which is the canonical mediator of growth hormone (GH) signaling. It is now recognized that GH has important actions as a neurotrophic factor. Therefore, we analyzed the effects of KLF13 on the activity of the JAK/STAT signaling pathway in the hippocampus-derived cell line HT22. Results showed that KLF13 directly regulates the expression of several genes involved in the JAK-STAT pathway, including Jak1, Jak2, Jak3, and Socs1, by associating with their proximal gene promoters. In addition, it was found that in KLF13-deficient HT22 neurons, the expression of Jak1, Stat3, Socs1, Socs3, and Igf1 was dysregulated, exhibiting mRNA levels that went up to 7-fold higher than the control cell line. KLF13 displayed a differential effect on the GH-induced JAK/STAT pathway activity, decreasing the STAT3 branch while enhancing the STAT5 branch. In KLF13-deficient HT22 cells, the activity of the STAT3 branch was enhanced, mediating the GH-dependent augmented expression of the JAK/STAT output genes Socs1, Socs3, Igf1, and Bdnf. Furthermore, GH treatment increased both the nuclear content of KLF13 and Klf13 mRNA levels, suggesting that KLF13 could be part of the mechanisms that maintain the homeostatic state of this pathway. These findings support the notion that KLF13 is a regulator of JAK/STAT activity. Full article

Pancreatic beta cell function is an important component of glucose homeostasis. Here, we investigated the function of PIMT (PRIP-interacting protein with methyl transferase domain), a transcriptional co-activator binding protein, in the pancreatic beta cells. We observed that the protein levels of PIMT, along with key beta cell markers such as PDX1 (pancreatic and duodenal homeobox 1) and MafA (MAF bZIP transcription factor A), were reduced in the beta cells exposed to hyperglycemic and hyperlipidemic conditions. Consistently, PIMT levels were reduced in the pancreatic islets isolated from high fat diet (HFD)-fed mice. The RNA sequencing analysis of PIMT knockdown beta cells identified that the expression of key genes involved in insulin secretory pathway, Ins1 (insulin 1), Ins2 (insulin 2), Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Kcnn1 (potassium calcium-activated channel subfamily N member 1), Rab3a (member RAS oncogene family), Gnas (GNAS complex locus), Syt13 (synaptotagmin 13), Pax6 (paired box 6), Klf11 (Kruppel-Like Factor 11), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1) was attenuated due to PIMT depletion. PIMT ablation in the pancreatic beta cells and in the rat pancreatic islets led to decreased protein levels of PDX1 and MafA, resulting in the reduction in glucose-stimulated insulin secretion (GSIS). The results from the immunoprecipitation and ChIP experiments revealed the interaction of PIMT with PDX1 and MafA, and its recruitment to the insulin promoter, respectively. Importantly, PIMT ablation in beta cells resulted in the nuclear translocation of insulin. Surprisingly, forced expression of PIMT in beta cells abrogated GSIS, while Ins1 and Ins2 transcript levels were subtly enhanced. On the other hand, the expression of genes, PRIP/Asc2/Ncoa6 (nuclear receptor coactivator 6), Pax6, Kcnj11, Syt13, Stxbp1 (syntaxin binding protein 1), and Snap25 (synaptosome associated protein 25) associated with insulin secretion, was significantly reduced, providing an explanation for the decreased GSIS upon PIMT overexpression. Our findings highlight the importance of PIMT in the regulation of insulin synthesis and secretion in beta cells. Full article

The kruppel-like factor (KLF) gene family is a group of transcription factors containing highly conserved zinc-finger motifs, which play a crucial role in cell proliferation and differentiation. Chicken has been widely used as a model animal for analyzing gene function, however, little is known about the function of the KLF gene family in chickens. In this study, we performed genome-wide studies of chicken KLF genes and analyzed their biological and expression characteristics. We identified 13 KLF genes from chickens. Our phylogenetic, motif, and conserved domain analyses indicate that the KLF gene family has remained conserved through evolution. Synteny analysis showed the collinear relationship among KLFs, which indicated that they had related biomolecular functions. Interaction network analysis revealed that KLFs worked with 20 genes in biological processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that KLF2 was involved in Apelin and Forkhead Box O (FOXO) signaling pathways. Moreover, qPCR showed that 13 KLF genes were expressed in the nine selected tissues and displayed various gene expression patterns in chickens. RNA-seq showed that KLF3 and KLF10 genes were differentially expressed in the normal and high-fat diet fed groups, and KLF4, KLF5, KLF6, KLF7, KLF9, KLF12, and KLF13 genes were differentially expressed between undifferentiated and differentiated chicken preadipocytes. Besides, RNA-seq also showed that KLF genes displayed different expression patterns in muscle at 11 and 16 embryonic days old, and in 1-day-old chickens. These results indicated that the KLF genes were involved in the development of muscle and fat in chickens. Our findings provide some valuable reference points for the subsequent study of the function of KLF genes. Full article

Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (−log₁₀(9.54 × 10⁻²¹) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness. Full article